Review

Severe Acute Respiratory Syndrome Coronavirus as an Agent of Emerging and Reemerging Infection

Vincent C. C. Cheng, Susanna K. P. Lau, Patrick C. Y. Woo, Kwok Yung Yuen
DOI: 10.1128/CMR.00023-07

SUMMARY

SUMMARY Before the emergence of severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) in 2003, only 12 other animal or human coronaviruses were known. The discovery of this virus was soon followed by the discovery of the civet and bat SARS-CoV and the human coronaviruses NL63 and HKU1. Surveillance of coronaviruses in many animal species has increased the number on the list of coronaviruses to at least 36. The explosive nature of the first SARS epidemic, the high mortality, its transient reemergence a year later, and economic disruptions led to a rush on research of the epidemiological, clinical, pathological, immunological, virological, and other basic scientific aspects of the virus and the disease. This research resulted in over 4,000 publications, only some of the most representative works of which could be reviewed in this article. The marked increase in the understanding of the virus and the disease within such a short time has allowed the development of diagnostic tests, animal models, antivirals, vaccines, and epidemiological and infection control measures, which could prove to be useful in randomized control trials if SARS should return. The findings that horseshoe bats are the natural reservoir for SARS-CoV-like virus and that civets are the amplification host highlight the importance of wildlife and biosecurity in farms and wet markets, which can serve as the source and amplification centers for emerging infections.

INTRODUCTION

Severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) is a novel virus that caused the first major pandemic of the new millennium (89, 180, 259). The rapid economic growth in southern China has led to an increasing demand for animal proteins including those from exotic game food animals such as civets. Large numbers and varieties of these wild game mammals in overcrowded cages and the lack of biosecurity measures in wet markets allowed the jumping of this novel virus from animals to human (353, 376). Its capacity for human-to-human transmission, the lack of awareness in hospital infection control, and international air travel facilitated the rapid global dissemination of this agent. Over 8,000 people were affected, with a crude fatality rate of 10%. The acute and dramatic impact on health care systems, economies, and societies of affected countries within just a few months of early 2003 was unparalleled since the last plague. The small reemergence of SARS in late 2003 after the resumption of the wildlife market in southern China and the recent discovery of a very similar virus in horseshoe bats, bat SARS-CoV, suggested that SARS can return if conditions are fit for the introduction, mutation, amplification, and transmission of this dangerous virus (45, 190, 215, 347). Here, we review the biology of the virus in relation to the epidemiology, clinical presentation, pathogenesis, laboratory diagnosis, animal models or hosts, and options for treatment, immunization, and infection control.

TAXONOMY AND VIROLOGY OF SARS-CoV

SARS-CoV is one of 36 coronaviruses in the family Coronaviridae within the order Nidovirales. Members of the Coronaviridae are known to cause respiratory or intestinal infections in humans and other animals (Fig. 1). Despite a marked degree of phylogenetic divergence from other known coronaviruses, SARS-CoV together with bat SARS-CoV are now considered group 2b coronaviruses (190, 282). Primary isolation of SARS-CoV was achieved by inoculation of patients' specimens into embryonal monkey kidney cell lines such as FRhK-4 or Vero E6 cell lines, which produced cytopathic changes at foci, where cells become round and refractile within 5 to 14 days (259). These initial cytopathic changes spread throughout the cell monolayers, leading to cell detachment within 24 to 48 h. Subcultures can be made on Vero (monkey kidney), Huh-7 (liver cancer) (301), CACO-2 (colonic carcinoma) (79) or other colorectal cancer, MvLu (mink lung epithelial) (104), and POEK and PS (pig) cell lines (122). Transmission electron microscopy of infected cell lines showed characteristic coronavirus particles within dilated cisternae of rough endoplasmic reticulum and double-membrane vesicles. Clusters of extracellular viral particles adhering to the surface of the plasma membrane were also seen. Negatively stained electron microscopy showed viral particles of 80 to 140 nm with characteristic surface projections of surface proteins from the lipid envelope (89, 180, 259). SARS-CoV has a higher degree of stability in the environment than other known human coronaviruses (91, 276). It can survive for at least 2 to 3 days on dry surfaces at room temperature and 2 to 4 days in stool (276). The electron microscopic appearance and genome order of 5′-replicase (Orf1ab)-structural proteins (spike [S]-envelope [E]-membrane [M]-nucleocapsid [N])-poly(T)-3′ are similar to those of other members of the Coronaviridae (236). Similar to other coronaviruses, it is an enveloped positive-sense single-stranded RNA virus with a genome size of almost 30 kb (Fig. 2). The genome is predicted to have 14 functional open reading frames (ORFs) (290). Their functions and putative roles are outlined in Table 1. Two large 5′-terminal ORFs, ORFs 1a and 1b, encode 16 nonstructural proteins, 7 of which are likely to be involved in the transcription and replication of the largest genome among all RNA viruses (92, 95, 158, 166, 242, 284, 309, 316, 343, 414). The two proteases are involved in posttranslational proteolytic processing of the viral polyprotein (5, 15, 121, 224, 394). The surface S protein is involved in the attachment and entry of the host cell and is therefore the main target for neutralizing antibody and antiviral peptides (159, 206, 227, 301, 334). N together with M, E, and Orf7a are involved in the assembly of the virion (97, 147, 150, 245, 359). Orf3a is an ion channel protein that is likely to be involved in viral budding and release (234). Analysis of genome sequences of many isolates of SARS-CoV from humans with civet SARS-CoV and bat SARS-CoV showed that the most variable genes with nucleotide homologies of less than 90% are the S gene, Orf3, Orf8, nsp2, nsp3, and nsp4 (190, 215, 282). Deletions of 82 and 415 nucleotides in Orf8 were found in some human isolates, whereas a unique 29-nucleotide signature insertion in Orf8 can be found in animal isolates (64, 117). Therefore, the more conserved Orf1b is generally chosen to be the molecular target for the design of clinical diagnostic tests rather than these less conserved regions.

FIG. 1.
FIG. 1.

Phylogenetic tree of 28 coronaviruses with complete protein sequences of helicase. Their accession numbers are shown in parentheses. Italic type indicates the complete genome accession numbers since helicase protein sequence accession numbers of these coronaviruses are not available. The helicase of another eight coronaviruses of spotted hyena, cheetah, ferret, puffinosis, rat, pigeon, goose, and duck are not included because no complete protein sequence is available. The classification of Asian leopard cat coronavirus is undefined. The tree was constructed by the neighbor-joining method using clustalX 1.83. The scale bar indicates the estimated number of substitutions per 50 nucleotides. (Data are from references 265, 326, 339, 367, 368, and 375.)

FIG. 2.
FIG. 2.

Genome arrangement of SARS-CoV. Gray boxes indicate 3CL protease (3CLpro), polymerase (pol), spike (S), envelope (E), membrane (M), and nucleocapsid (N) genes.

View this table:
TABLE 1.

Nomenclature and functional characteristics of SARS-CoV gene products and their interactions with host cells in disease pathogenesis

VIRAL LIFE CYCLE

Trimers of the S protein form the peplomers that radiate from the lipid envelope and give the virus a characteristic corona solis-like appearance under an electron microscope. S is a class I fusion protein that consists of the amino-terminal S1 and carboxyl-terminal S2 subunits connected by a fusion peptide. The two subunits are indispensable for receptor binding and membrane fusion, respectively. The receptor binding domain of S1 has been mapped to residues 318 to 510 (9, 365). The binding of S1 to the cellular receptor will trigger conformational changes, which collocate the fusion peptide upstream of the two heptad repeats of S2 to the transmembrane domain, and, finally, fusion of the viral and cellular lipid envelopes. Moreover, this process could be facilitated by the infected cell membrane-associated protease, such as factor Xa, which can cleave S into S1 and S2. This proteolytic cleavage is specifically inhibited by a protease inhibitor, Ben-HCl (90).

The key receptor of the host cell attached by S is angiotensin-converting enzyme 2 (ACE2), which is a metalloprotease expressed in the cells of the lung, intestine, liver, heart, vascular endothelium, testis, and kidney (119). Since ACE2 was shown to protect against acute lung injury in a mouse model and since the binding of the S protein to host cells results in the downregulation of ACE2, this mechanism may contribute to the severity of lung damage in SARS (181). Cells expressing some lectins, including DC-SIGN, L-SIGN, and LSECtin, have been shown to augment the cellular entry of pseudotype virus expressing S but only in the concomitant presence of ACE2 (40, 107, 162, 398). Nonsusceptible cells expressing these lectins in the absence of ACE2, such as dendritic cells, were able to promote the cell-mediated transfer of SARS-CoV to susceptible cells (40). Although lysosomotropic agents can block viral entry, which indicates that endosomal acidification is required for entry, the activation of the S protein by protease can bypass this inhibition and result in cell-to-cell fusion. Despite the role of the pH-sensitive endosomal protease cathepsin L in the entry pathway (151, 300), viral culture does not require pretreatment with trypsin. However, this pH-sensitive cathepsin L may be a target for agents such as chloroquine, which elevates endosomal pH (174, 341).

The process of viral disassembly in the cytoplasm for the release of viral RNA for translation and replication remains elusive. Translation starts with two large polyproteins from Orf1a and Orf1ab, which are posttranslationally cleaved by the two viral proteases into nsp1 to nsp16. These cleavage products form the replication-transcription complex, which replicates the viral genome and transcribes a 3′-coterminal nested set of eight subgenomic RNAs. It is therefore conceivable that infected cells contain a higher number of transcripts containing genes towards the 3′ terminus of the viral genome. On this basis, reverse transcriptase PCR (RT-PCR) using the N gene may have a better sensitivity than those using the other genes.

As in other coronaviruses, SARS-CoV may attach by the hydrophobic domains of their replication machinery to the limiting membrane of autophagosomes and form double-membrane vesicles. Once sufficient viral genomic RNA and structural proteins are accumulated, viral assembly by budding of the helical nucleocapsid at the endoplasmic reticulum to the Golgi intermediate compartment occurs. Here, the triple-membrane-spanning M protein interacts with the N protein and viral RNA to generate the basic structure. It also interacts with the E and S proteins to induce viral budding and release. Unlike other coronaviruses, the M protein of SARS-CoV also incorporates another triple-membrane-spanning protein of Orf3a into the virion (161). The N protein is the most abundantly expressed viral protein in infected cells in which the mRNA levels were amplified 3 to 10 times higher at 12 h postinfection than other structural genes (138) and is therefore an important target for immunohistochemistry and antigen detection in clinical specimens. Various diagnostic tests, antiviral agents, and vaccines are designed on the basis of our understanding of the structure and function of the various viral proteins involved in the life cycle of this virus.

SEQUENCE OF THE SARS EPIDEMIC AND MOLECULAR EVOLUTION OF THE VIRUS

Sequence of EventsSARS was the first known major pandemic caused by a coronavirus. During the epidemic in 2003, 8,096 cases with 774 deaths had occurred in over 30 countries among five continents (89, 117, 144, 180, 182, 197, 236, 250, 259, 260, 270, 290, 292, 303, 336, 377). The disease emerged in late 2002, when an outbreak of acute community-acquired atypical pneumonia syndrome was first noticed in the Guangdong Province (Table 2). Retrospective surveillance revealed severe cases of the disease in five cities around Guangzhou over a period of 2 months (431). The index case was reported in Foshan, a city 24 km away from Guangzhou. The second case involved a chef from Heyuan who worked in a restaurant in Shenzhen. The patient had regular contact with wild game food animals. His wife, two sisters, and seven hospital staff members who had contact with him were also affected. From 16 November 2002 to 9 February 2003, a total of 305 cases were reported in mainland China, with 105 of those cases involving health care workers. The devastating pandemic started in Hong Kong, Special Administrative Region (HKSAR), when a professor of nephrology from a teaching hospital in Guangzhou who had acquired the disease from his patients came to HKSAR on 21 February 2003. Within a day, he transmitted the infection to 16 other people in the hotel where he resided. His brother-in-law, one of the secondary cases, underwent an open lung biopsy from which the etiological agent was discovered and first isolated (259). It was a novel coronavirus, named SARS-CoV.

View this table:
TABLE 2.

Sequence of events and molecular evolution of SARS-CoV throughout the epidemica

The secondary cases unknowingly carried the disease to hospitals in the HKSAR and to other countries and continents including Vietnam, Canada, Singapore, the Philippines, the United Kingdom, the United States, and back again to China. Carlo Urbani, a physician working at the World Health Organization (WHO) office in Hanoi, Vietnam, was the first to notify the WHO of cases outside Guangdong after witnessing an explosive nosocomial outbreak of SARS in a hospital in Hanoi, which resulted from a person who had returned from the hotel in HKSAR. Carlo Urbani's description of the disease, to which he later succumbed, alerted health authorities throughout the world and accelerated collaborative research to identify the virus and combat the disease (281).

Molecular EvolutionSoon after the isolation of SARS-CoV, SARS-CoV-like viruses were found in palm civets and a raccoon dog from wild-animal markets in the Guangdong Province of China (117), suggesting that these animals could be the source of human infections. As a result, massive numbers of palm civets were culled to remove sources for the reemergence of SARS in Guangdong in January 2004. The virus was found in many civets and raccoon dogs from the wildlife market prior to culling but not in over 1,000 civets later sampled at 25 farms in 12 provinces (168). The evolutionary starting point was a prototype group consisting of three viral genome sequences of animal origin. This prototype group representing low-pathogenicity virus has seven single-nucleotide variation (SNV) sites that caused six amino acid changes, at positions 147, 228, 240, 479, 821, and 1080 of the S protein, which were involved in generating the early phase of the 2002 and 2003 epidemic. One of these was found in the first SARS patient in the subsequent epidemic of 2003 to 2004. A further 14 SNVs caused 11 amino acid residue changes, at positions 360, 462, 472, 480, 487, 609, 613, 665, 743, 765, and 1163. This resulting high-pathogenicity virus group caused the middle phase of the epidemic of 2003. Finally, the remaining six SNVs caused four amino acid changes, at positions 227, 244, 344, and 778, which resulted in the group of viruses responsible for the late phase and the global epidemic (168). The neutral mutation rate of this virus during the epidemic in 2003 is almost constant, at around 8 × 10−6 nt−1 day−1, which is similar to those of most known RNA viruses (64, 304). The most recent common ancestor was estimated to be present around mid-November, which is epidemiologically compatible with the first case of SARS found in Foshan.

After the epidemic was over, a second interspecies-jumping event occurred in late 2003 to early 2004, resulting in the reemergence of four human cases in China (45, 347). These four cases were believed to be due to an independent interspecies transmission event, instead of residual cases of the major epidemic, because of the much lower affinity for human ACE2 (hACE2) of the S proteins of SARS-CoV isolated from these patients and palm civets than that of the major 2003 epidemic isolates from SARS patients, which utilized both human and palm civet ACE2 efficiently (216). Since S contains the receptor binding domain for the host receptor and is immunogenic, it is under selection in the host and becomes the most rapidly evolving protein, with most mutations located in the S1 domain and especially the receptor binding domain. Bioinformatic analysis has identified three key amino acid residues at positions 360, 479, and 487 that are responsible for host-specific binding (17). Most human isolates in the 2003 epidemic have N479 and T487 in their S, whereas most civet isolates have K/R479 and S487. The low affinity of the S proteins bearing K479 and S487 combinations for hACE2 was confirmed by pseudotype binding assays. However, the human and civet isolates of the outbreak of 2003 to 2004 had N479 and S487, which suggested that this is an intermediate stage of mutation of the S protein. Further change to the N479 and T487 combination will allow efficient human-to-human transmission (275). Apart from the subsequent minor outbreak, three laboratory-associated outbreaks were reported in Singapore, Taiwan, and Beijing from September 2003 to May 2004 (221, 251, 252, 256). In Beijing, the outbreak also involved secondary and tertiary cases.

Phylogenetic analysis of the S protein of 139 SARS-CoV isolates in the Hong Kong outbreak showed that several introductions of viruses had occurred but that only one of them was associated with the major outbreak in HKSAR and the rest of the world (116). Some of the strains found in the early stages of the outbreak were phylogenetically distinct from the major cluster and were closer to some of the Guangdong and Beijing strains. This concurred with the fact that the index patient of the HKSAR outbreak was a Guangzhou medical doctor who had traveled to HKSAR. Another molecular epidemiological study of the Guangdong outbreak suggested that the disease spread from Guangdong to HKSAR and the rest of the world, and the index case was a chef who handled game animals (431). Subsequent animal surveillance in China recovered coronavirus isolates that had 99.8% nucleotide identity with SARS-CoV (117). A characteristic 29-bp insertion between Orf8a and Orf8b (also initially known as Orf10 and Orf11) was found in these animal isolates (117, 302). This 29-nucleotide segment was deleted either before or soon after crossing the species barrier to humans. The biological effect of this deletion remains elusive. A number of SARS-CoV isolates in the later stages of the epidemic showed larger deletions around this site (64). Two independent molecular epidemiological studies comparing the complete genomes of 12 and 63 virus isolates also found evidence of strong positive selection at the beginning of the epidemic, which was followed by a purifying selection, as indicated by the amino acid substitution rate at S, Orf3a, and nsp3 (64, 304, 402). Both studies suggested that molecular adaptation of the virus had occurred after interspecies transmission from animals to humans. In the small outbreak in Guangzhou in 2004, all four human isolates belonged to a separate sublineage of the concurrent animal isolates that were distinct from the human pandemic or animal viruses in 2003. Although SARS-CoV is distinct from the three existing groups of coronaviruses, it may be closer to group II because 19 out of 20 cysteines found in the S1 domain of the S protein are spatially conserved compared with the group II consensus sequence, whereas only five cysteine residues are conserved compared with those of groups I and III (93, 302). Since coronaviruses are believed to have coevolved with their animal hosts, it is possible that rats, mice, and cattle harboring group II coronaviruses are more likely to be the animal host for SARS-CoV than cats, which harbor group I coronavirus. However, when a comparison of the phylogenetic trees for 11 known host species and nucleocapsid sequences of 36 coronaviruses was done using an inference approach with sliding-window analysis, there was statistical incongruence, which indicates multiple host species shifts between the coronaviruses of many animals that are phylogenetically distant (283). Thus, it would not be too unexpected if other mammals are the true animal reservoir rather than mice and rats. Nevertheless, civets and other related mammals had at least served as a major amplification host in the markets of southern China irrespective of the original animal reservoir. The control of these animals and the markets played a pivotal role in the epidemiological control of SARS (304). In view of the low rate of detection of SARS-CoV in wild and farm civets (338), in contrast to a very high rate in caged civets in wildlife markets, efforts were made to find the natural reservoir of SARS-CoV in birds, pig, cattle, sheep, mice, and rats, which all turned out to be negative. However, SARS-CoV-like viruses with around 90% genomic identity with SARS-CoV were independently discovered in horseshoe bats (Rhinolophus spp.) in HKSAR and mainland China (190). The high seroprevalence and viral load of infected Chinese horseshoe bats, Rhinolophus sinicus, strongly suggested that bats are the natural reservoir of SARS-CoV-like viruses, similar to the situation of fruit bats carrying Hendra virus or Nipah virus (363).

EPIDEMIOLOGICAL CHARACTERISTICS

The epidemiological linkage of the initial human cases of the 2003 pandemic to wild game animals suggested that SARS-CoV is zoonotic in origin (431). The isolation of SARS-CoV-like viruses from palm civets and subsequently horseshoe bats further supported this contention (117, 190). It was reported that a seroprevalence rate of about 80% was found in civets in animal markets in Guangzhou (338). However, person-to-person transmission has been the primary mode of spread of the epidemic, which has occurred in health care facilities, workplaces, homes, and public transportation. The most important route of person-to-person spread appears to be direct or indirect contact of the mucosae with infectious respiratory droplets or fomites (296). SARS-CoV has been detected in respiratory secretions, feces, urine, and tears of infected individuals (42, 229). Nosocomial transmission of SARS was facilitated by the use of nebulizers, suction, intubation, bronchoscopy, or cardiopulmonary resuscitation on SARS patients, when large numbers of infectious droplets were generated (70, 197, 340). In fact, almost half of the SARS cases in HKSAR were nosocomial infections that were acquired within health care facilities and institutions (202). The attack rate among health care workers was higher where the number of SARS patients was greater (187). Although airborne transmission is considered uncommon, a unique form of airborne transmission was considered a likely explanation for a large community outbreak in a private housing estate called Amoy Garden in HKSAR. Contaminated aerosols generated in toilets by exhaust fans coupled with dried U traps of sewage drains, which ascended the light well connecting different floors, caused an explosive outbreak affecting hundreds of people (71, 405). The presence of viruses in stool, often with high viral loads (156, 258), also suggested the possibility of feco-oral transmission, although this has not been proven conclusively. It was suggested that SARS was transmitted in commercial aircraft during the epidemic. Out of a total of 40 flights investigated, 5 were associated with probable in-flight SARS transmission, affecting 37 passengers (254). Most of the affected passengers sat within five rows of the index case. The overall risk of transmission appears to be low, at around 1 in 156 (358). In the largest incident, during a 3-h flight carrying 120 passengers traveling from HKSAR to Beijing, a superspreading event (SSE) infected 22 passengers (254). The pattern of involvement was atypical, considering the short duration of exposure of 3 h and the widespread involvement of patients sitting within seven rows in front of and five rows behind the index case. Although airborne transmission was considered to be a possible explanation, other potential modes of transmission, such as contact of passengers with the index case before or after the flight, cannot be excluded, especially since 17 out of the 22 people infected were from two tourist groups (254). In another study, a SARS patient traveled between HKSAR and European countries during the presymptomatic and early symptomatic period, and no transmission among passengers seated in close proximity to the index patient was found, suggesting that in-flight transmission of SARS is not common (23). Symptomatic SARS patients appeared to transmit infections on board much more readily than presymptomatic ones (23, 254, 358). Initiation of screening procedures to detect people with fever prior to boarding has been used in an attempt to reduce the risk of in-flight transmission of SARS, but the efficacy is still uncertain (342).

In 17 studies that reported on seroepidemiology, the seroprevalence varied from 0 to 1.81% for the general population, 0 to 2.92% for asymptomatic health care workers, 0 to 0.19% for asymptomatic household contacts, and 12.99 to 40% for asymptomatic animal handlers (28, 37, 45, 69, 117, 141, 198, 201, 203, 207, 209, 228, 352, 369, 387, 406, 429). The last finding is quite expected, since frequent zoonotic challenges by low-level-pathogenic strains of SARS-CoV before 2003 in animal handlers of southern China would probably have caused such a high seroprevalence in this at-risk group. Genuine asymptomatic infection with antigenemia detected by enzyme immunoassay (EIA) and seroconversion confirmed by neutralization antibody assay was documented in a restaurant worker who worked in the same restaurant as the index case of the outbreak of 2003 to 2004 (45). However, in 2003, sustained exposure of the animal handlers to these infected civets and other wild animals would result in the introduction of a moderately transmissible and more virulent SARS-CoV strain, which would have mutated from the animal strain and adapted to infect humans more efficiently. The result was a massive global outbreak, but the overall asymptomatic infection rate was still relatively low with this more virulent human-adapted virus in the general population, health care workers, and household contacts. A meta-analysis gave overall seroprevalence rates of 0.1% for the general population and 0.23% for health care workers (203). It is also important to remember that these seroprevalence studies are not directly comparable since different serological methods of various sensitivities or specificities were used with or without confirmation by another test. Thus, the true incidence of asymptomatic infection remains elusive.

The incubation period of SARS is 2 to 14 days, although occasional cases with longer incubation periods have been reported (41). The average number of secondary cases resulting from a single case was two to four (225, 285). Unlike influenza virus, where the patients were most infectious in the first 2 days of illness, transmission from symptomatic SARS patients usually occurred on or after the fifth day of onset of disease, which is in line with the rising viral load in nasopharyngeal secretions that peaked at around day 10 (258). There have been speculations about the incidence of SARS and ambient temperature (319), but a definite seasonality could not be concluded. SSEs have been noted to play an important role in the propagation of the SARS outbreak, which gives rise to a disproportionate number of secondary cases, as in the Amoy Garden of HKSAR. A study comparing the clinical and environmental features of SSE and non-SSE cases showed that SSEs were likely to be related to a combination of factors including delayed isolation, admission to a nonisolation ward, and severe disease at the time of isolation (53).

CLINICAL FEATURES

The typical clinical presentation of SARS is that of viral pneumonia with rapid respiratory deterioration (Table 3). Fever, chills, myalgia, malaise, and nonproductive cough are the major presenting symptoms, whereas rhinorrhea and sore throat are less frequently seen (7, 21, 37, 149, 197, 258, 259, 270, 278, 336, 411, 425). Clinical deterioration, often accompanied by watery diarrhea, commonly occurs 1 week after the onset of illness (58, 258). Similar to other causes of atypical pneumonia, physical signs upon chest examination are minimal compared with the radiographical findings. Chest radiographs typically show ground-glass opacities and focal consolidations, especially in the periphery and subpleural regions of the lower zones. Progressive involvement of both lungs is not uncommon (113, 148, 184, 362). Shifting of radiographic shadows and spontaneous pneumomediastinum may occur (74, 258). A retrospective analysis of serial chest radiographs in all SARS patients from HKSAR showed that the initial extent and progression of radiographic opacities may be useful for prognostic prediction (6).

View this table:
TABLE 3.

Correlation between clinical, virological, immunological, and histopathological findings

Diarrhea is the most common extrapulmonary manifestation, followed by hepatic dysfunction; dizziness, which may be related to diastolic cardiac impairment and pulmonary arterial thrombosis; abnormal urinalysis; petechiae; myositis; neuromuscular abnormalities; and epileptic fits (44, 58, 188, 211, 248, 335, 346, 383). The elderly may present atypically without fever or respiratory symptoms (68, 361). While infections in children appear to be milder than those in adults (20, 144, 183), SARS in pregnant women carries a significant risk of mortality (364, 410). Higher nasopharyngeal and serum viral loads were associated with oxygen desaturation, mechanical ventilation, and mortality; higher stool viral loads were associated with diarrhea; and higher urine viral loads were associated with abnormal urinalysis (58, 75, 156). The significant correlation of the viral loads in these specimens to the severity of clinical or laboratory findings suggested that extrapulmonary viral replication was contributing to clinical manifestations (156).

As for hematological parameters, peripheral blood lymphopenia and elevated hepatic parenchymal enzymes are common with or without thrombocytopenia or increases in D dimers and activated partial thromboplastin time (197). About 20% to 30% of patients developed respiratory failure requiring mechanical ventilation, and the overall mortality rate was around 15%. Age, presence of comorbidities, increased lactate dehydrogenase level, hypouricemia, acute renal failure, more extensive pulmonary radiological involvement at presentation, and a high neutrophil count at the time of admission are poor prognostic indicators (153, 197, 385). Restrictive lung function abnormalities due to residual lung fibrosis and muscle weakness are common in the convalescent phase (34, 247, 255). Among survivors of SARS in HKSAR 1 year after illness, significant impairment in diffusion capacity was noted in 23.7% of studied subjects. The exercise capacity and health status of SARS survivors were also remarkably lower than those of the healthy population (154). A study on the pathological changes of testes from six patients who died of SARS indicated that orchitis was also a complication and suggested that reproductive functions in male patients who recovered from SARS should be monitored (388). Depression and posttraumatic stress disorder are especially common among health care workers and patients with affected family members (57, 66, 238, 310). Complications due to the use of corticosteroids including psychosis, adrenal insufficiency, and avascular osteonecrosis were also reported (36, 112, 145, 195, 200).

HISTOPATHOLOGICAL CHANGES OF SARS

Histological ChangesAcute diffuse alveolar damage with air space edema was the most prominent feature in patients who died before the 10th day after onset of illness (99, 250). Hyaline membranes, interstitial edema, interstitial infiltrates of inflammatory cells, bronchiolar injury with loss of cilia, bronchiolar epithelial denudation, and focal deposition of fibrin on the exposed basement membranes were other observed features (157). Patients who died after the 10th day of illness exhibited a mixture of acute changes and those of the organizing phase of diffuse alveolar damage. There was interstitial and airspace fibroblast proliferation, type II pneumocyte hyperplasia, and squamous metaplasia of bronchial epithelium. The alveolar spaces contained a combination of macrophages, desquamated pneumocytes, and multinucleated giant cells. Hemophagocytosis in the alveolar exudates and thrombosis of venules were noted in some cases. Other pulmonary complications might include secondary bacterial bronchopneumonia and invasive aspergillosis (345). Systemic vasculitis involving the walls of small veins with edema, fibrinoid necrosis, and infiltration by monocytes, lymphocytes, and plasma cells were noted in one report (87).

No tissue destruction or severe inflammatory process associated with viral infection was noted in other organs or tissues, but viral particles could be detected in pneumocytes and enterocytes by in situ hybridization (331). Inflammation, cellular apoptosis, or microvillus atrophy of a significant degree was not found in the intestinal mucosa to account for the watery diarrhea. Immunohistochemical staining showed the presence of viral nucleoproteins in type II pneumocytes and occasionally pulmonary macrophages. Necrosis or atrophy in the lymphoid tissue of lymph nodes and white pulp of the spleen are commonly observed extrapulmonary pathologies.

Immunological ProfilesFlow cytometric examination of the peripheral blood at the time of admission before the use of steroid showed decreases in levels of dendritic cell subsets, natural killer cells, CD4+ and CD8+ T lymphocytes, and B lymphocytes (82, 213, 420). A study of three SARS patients suggested that a self-limiting or abortive infection of peripheral blood mononuclear cells can occur, as evident by the presence of minus-strand RNA, the replicative intermediate of the virus during the initial week of illness (208). Studies of the cytokine profile of SARS patients showed conflicting results, which may be due to the use of many immunomodulators including steroids. However, those studies generally showed consistent and significant elevations of the plasma chemokines gamma interferon (IFN-γ)-inducible protein 10 (IP10 [CXCL10]), monocyte chemotactic protein 1 (MCP-1 [CCL2]), and interleukin-8 (IL-8). In some studies, levels of the Th1-related cytokines IFN-γ and IL-12 and the inflammatory cytokines IL-1β and IL-6, which can induce an intense inflammatory response, were also increased (63, 152, 163, 165, 325, 360). In one study, patients with severe disease tended to have increased plasma levels of IFN-α, IFN-γ, and CXCL10 and decreased levels of IL-12p70, IL-2, and tumor necrosis factor alpha (TNF-α) during the acute phase. In the late phase, patients with severe disease had significantly increased plasma chemokine levels of IL-8, CXCL10, and CCL2 but decreased cytokine levels of IL-12p70, IL-2, TNF-α, and IFN-γ compared with mild cases of SARS (26). These host responses may account for the recruitment and accumulation of alveolar macrophages and polymorphs and the activation of Th1 cell-mediated immunity by the stimulation of natural killer and cytotoxic T lymphocytes, respectively. Since SARS-CoV appears to evade the triggering of IFN-α and IFN-β in human macrophages in vitro (61, 280), the lack of an antiviral innate immune response may permit uncontrolled viral replication with progressive increases in viral load and the accompanying proinflammatory systemic response. This situation continues into the second week of illness until the appearance of the adaptive immune response, which brings viral replication under control. Moreover, comparative transcriptomal microarray analysis showed that SARS-CoV rather than CoV-229E markedly upregulated genes associated with apoptosis, inflammation, the stress response, and procoagulation during the early phase of infection of a human liver cancer cell line (Huh7) (322). Both observations help to explain the clinical severity of SARS in relation to the high viral load at up to 2 weeks of illness and the intense inflammatory response as evident from serum cytokine profiles and histopathology. The majority of SARS patients resolved the proinflammatory cytokine and chemokine responses at the acute phase and expressed adaptive immune genes. In contrast, patients who later succumbed showed deviated IFN-stimulated gene and immunoglobulin gene expression levels, persistent chemokine levels, and deficient anti-SARS spike antibody production. It was speculated that unregulated IFN responses during the acute phase may lead to a malfunction of the switch from innate immunity to adaptive immunity. Indeed, recovered patients were found to have higher and sustainable levels of N-specific antibody and S-specific neutralizing antibody responses, whereas patients who later succumbed had an initial rise and then a fall in antibody levels just before death, suggesting that antibody response is likely to play an important role in determining the ultimate disease outcome (417).

PATHOGENESIS, IMMUNE RESPONSE, AND HOST SUSCEPTIBILITY

Interaction between Viral and Cellular FactorsThe exact mechanism of how the virus produces damage at cells, tissue, and organs to clinical levels remains elusive. Similar to other viruses such as influenza A virus, Nipah virus, or Ebola virus, SARS-CoV must possess the ability to evade the innate antiviral response of the cells in order to replicate efficiently in the host. Transfection experiments with Orf3b, Orf6, and N in 293T cells showed that these viral proteins are IFN antagonists that can interfere with the synthesis of IFN and its downstream signaling pathways (178). However, this cannot explain the apparent discrepancy of IFN-β/α production in infected human intestinal Caco-2 cell line (253) and the lack of such production in SARS patients' peripheral blood mononuclear cells or in human primary macrophages abortively infected with SARS-CoV despite the activation of several IFN-stimulated genes in the latter case (61). On the other hand, this may explain the increased serum level of IFN of some SARS patients, which may have an intestinal source. Due to the lack of a type 2 pneumocyte cell line that is susceptible to SARS-CoV, the relevance of these findings cannot be ascertained for lung epithelial cells.

Once the virus can overcome the innate immune response at the cellular level, it can take over the host metabolic apparatus through the degradation of host mRNA by nsp1 and the modulation of the ubiquitination pathway of the host by nsp3 (15, 81, 192, 224, 279). Efficient viral replication ensues, and cell damage occurs by virus-induced cytolysis or immunopathology. Infected cell lines and postmortem lung tissues have shown cytopathic changes due to apoptosis, necrosis, or occasionally syncytium formation. Expression of nsp5, nsp10, Orf3a, Orf3b, Orf7a, Orf8a, E, M, and N in different cell lines by transfection can cause cellular apoptosis (Table 1). Expression of S in transfected cells can lead to syncytium formation with cells expressing ACE2 (181). Paradoxically, little cytopathic effect or inflammation was found in intestinal biopsy specimens of SARS patients despite marked viral replication seen with electron microscopy (205). The transcriptomal profile of infected Caco-2 cells showed a marked upregulation of the potent immunosuppressive cytokine transforming growth factor β and the antiapoptotic host cellular response, which may explain the noninflammatory secretory diarrhea and huge amount of viral shedding in stool (79). Therefore, the clinical or histopathological manifestations at various organs or tissues do not depend solely on the presence of the relevant receptor and coreceptors or the viral productivity as reflected by the viral load. The inflammatory and apoptotic responses of the cell triggered by the virus and the compensatory regenerative power or functional reserve of that organ may be equally important in determining the manifestations and the outcome of infection. nsp1 expression in human lung epithelial A549 cells can increase the expression of the chemokines IP10, CCL3, and CCL5 through the NF-κB pathway (192). This correlated well with the plasma chemokine profile of SARS patients and the immunohistochemical staining of infected lungs. IP10 expressed on pneumocytes is a potent chemoattractant for activated cytotoxic T lymphocytes, natural killer cells, and monocytes, which may therefore infiltrate the interstitium and alveoli of lungs of SARS patients. Administration of a recombinant S fragment between positions 324 and 688 and Orf3a expression in lung cells can excite the production of IL-8 (43, 169). The expression of N in transfected cells can also activate the Cox2 inflammatory cascade (393). If SARS-CoV can indeed suppress the early innate immune response of IFN-β/α in type 2 pneumocytes without activating the IFN-stimulated genes and therefore also allowing an uncontrolled viral replication in the adjacent cells, the concomitant activation of proinflammatory chemokines and cytokines would explain the dominant and highly fatal manifestation of SARS in the lungs.

Adaptive Immune ResponseIn general, specific serum antibody against whole SARS-CoV by indirect immunofluorescence or neutralization tests starts to appear at around day 7, plateaus at around the second month, and is maintained for over 12 months. Immunoglobulin M (IgM) and IgG appeared at around the same time, but the former was not detected after 2 to 3 months (371). Serum testing by recombinant nucleocapsid EIA can detect such an antibody as early as the fifth day after the onset of symptoms (46). The virus-specific T-cell-mediated immune response is not clearly defined. In one study, S-specific cell-mediated immunity mediated by CD4 and CD8 cells was found to last for more than 1 year (395).

Host SusceptibilitySome studies suggested a possible association of HLA-B*4601 with susceptibility to and severity of SARS among the Chinese population in Taiwan (223), but the finding was not confirmed in HKSAR SARS cases. Among the Chinese population in HKSAR, similar associations with HLA-B*0703 and the genetic variant ICAM3 Gly143 have been found (35, 249). Low-mannose-binding lectin producing the YB haplotype has an increased risk of acquiring SARS (160, 416). On the other hand, individuals with HLA-DRB1*0301 or that are homozygous for CLEC4M tandem repeats were found to be less susceptible to SARS-CoV infection (40, 249). However, the latter finding was strongly disputed in two subsequent studies (324, 430).

LABORATORY DIAGNOSIS OF SARS-CoV INFECTION

No pathognomonic signs or symptoms of SARS can be used to differentiate SARS from other causes of community- or hospital-acquired pneumonia. Etiological diagnosis and differentiation from other causes of atypical pneumonia can be made only by laboratory confirmation. A positive viral culture from respiratory, fecal, and, occasionally, urine or tissue specimens or a fourfold rise in the neutralizing antibody titer in serum samples taken upon admission and 28 days afterward is the most definitive evidence of infection. However, both viral culture and neutralizing antibody testing required a biosafety level 3 laboratory, which is not available in most hospitals. Rapid detection by nucleic acid amplification such as RT-PCR or antigen detection by EIA is the alternative. It is important that most of these rapid tests have never been thoroughly investigated in prospective field trials due to the short-lasting nature of the SARS epidemic. Thus, most of our data on these assays came from evaluations of stored clinical specimens. As for the collection of clinical specimens, although bronchoalveolar lavage fluid and lung biopsy tissue should be the ideal specimens at the onset of illness, such procedures are invasive and can be hazardous to health care workers. Nasopharyngeal aspirates and throat washings, taken with respiratory precautions and preserved in viral transport medium, remain the most important diagnostic specimens.

Nucleic Acid Amplification AssaysMost nucleic acid amplification tests are designed with the Orf1b or nucleoprotein gene (32, 56, 88, 108, 155, 189, 264, 266, 268, 349, 384, 391, 413). The latter gene has the theoretical advantage of being more abundant in infected cells and therefore of higher sensitivity, but this has not been clearly proven in clinical studies. Of these methods, real-time quantitative RT-PCR (Table 4) of the nasopharyngeal aspirate is the most sensitive and rapid method for aiding in clinical diagnosis and may achieve a sensitivity of 80% with good specificity even if it is collected within the first 5 days of illness (266). In-house qualitative RT-PCR tests are generally less sensitive and prone to contamination. Positive test results from a single sample must be confirmed by a repeat test detecting a different region of the SARS-CoV genome on the same sample. If possible, another repeat sample should also be tested to exclude false-positive results due to amplicon carryover. Since the viral load in nasopharyngeal aspirate usually peaked on the 10th day after the onset of symptoms, suspected SARS cases must have the tests repeated as the disease evolves to avoid false-negative results (32, 258). Stool specimens should also be routinely sent for testing since a very high percentage of patients develop diarrhea and shed virus during the second week of illness (58). Viral load determination of nasopharyngeal specimens or serum upon presentation might have clinical value, as it is an important prognostic factor (72, 73, 75, 156). Longitudinal monitoring of viral load would be an important part of any treatment trials in the future.

View this table:
TABLE 4.

Clinical evaluation of molecular diagnostic tests for SARS-CoV

Antigen Detection AssaysAntigen detection with monoclonal antibodies or monospecific polyclonal antibody against the N protein was found to be a sensitive and specific test for the diagnosis of SARS (Table 5). In a large study with sera collected from 317 SARS patients at different time points of illness, EIA detection of SARS N was performed using a panel of three monoclonal antibodies (46). Over 80% of SARS cases can be detected within the first 7 days after the onset of illness. As serum antibody levels started to rise at day 7, the sensitivity of the serum antigen assay progressively decreased to 0% at day 21 (46). Antigen detection with EIA in nonserum specimens is generally less sensitive than RT-PCR because the cutoff value is usually set at a much higher level than that of serum specimens to overcome the high background optical density values in nonserum specimens (189, 191).

View this table:
TABLE 5.

Clinical evaluation of antigen detection for SARS-CoV

Antibody Detection AssaysFor antibody testing (Table 6), the indirect immunofluorescent antibody test is more commonly performed than the neutralizing antibody test since the former involves minimal manipulation of infectious virus and therefore carries less risk of a biohazard. The test is generally not useful during the first week of illness. Single low-titer positive results can be related to cross-reactions with other human coronaviruses (31, 47). A recombinant nucleocapsid EIA may be used as a rapid screening test and possesses a higher sensitivity, with detection as early as day 5 after onset of illness (46), but again, false-positive results due to cross-reactions with HCoV-O43 and HCoV-229E can occur and require confirmation by Western blotting against the S polypeptide of SARS-CoV (372). Serum IgG, IgM, and IgA appeared at around the same time, between days 5 and 17 after the onset of symptoms, and paralleled the appearance of neutralizing antibody activity, but one study reported that IgM appeared 3 days earlier using an IgM capture EIA against nucleoprotein (404). The titer of neutralizing antibody peaked at days 20 to 30 and was sustained for a long time. It is interesting that the neutralizing antibody level of those who died peaked at day 14 and then started to fall, whereas those who survived had a sustained level of antibody (417). A new immunofluorescence assay using the S protein and a recombinant N-S fusion protein as an antigen has been described. The results are comparable to those obtained with whole-virus-based immunofluorescence assays (128, 235). The three laboratory outbreaks of SARS prompted the use of pseudotype viruses for research and neutralization antibody testing, but data on systematic evaluation are lacking.

View this table:
TABLE 6.

Clinical evaluation of antibody detection for SARS-CoV

CLINICAL MANAGEMENT AND ANTIVIRALS

Since there is no proven effective antiviral agent by randomized placebo control trial (Table 7), clinical management of SARS has relied largely upon supportive care. Broad-spectrum antimicrobial coverage for community-acquired pneumonia should be given while virological confirmation is pending. Such antibiotics should be stopped once the diagnosis of SARS is confirmed, but nosocomial infections as a result of prolonged intubation and the use of corticosteroids should be appropriately managed.

View this table:
TABLE 7.

Antiviral agents and immunomodulators against SARS-CoV in vivo

The correlation between viral loads and clinical outcome suggests that suppression of viral replication by effective antiviral drugs should be the key to preventing morbidity and mortality. However, in vitro susceptibility test results were often conflicting, as in the case of IFN-β1a (78, 137, 318) and IFN-α2b (308, 318). Nevertheless, it appears that IFN-β, IFN-αn1, IFN-αn3, and leukocytic IFN-α have some potential activity and warrant evaluation by clinical trials (50, 305, 426). Although a very high 50% cytotoxic concentration exceeding 1,000 mg/liter has been demonstrated for ribavirin (77), and although its low level of in vitro activity against SARS-CoV was initially attributed to cellular toxicity (318), ribavirin has good activity when tested in other human Caco-2 and pig kidney cell lines despite its lack of activity in Vero cells (243). The use of different cell lines, testing conditions, and virus strains may have contributed to these discrepancies.

Numerous other potential antiviral agents have been identified using different approaches (Table 8). Replication of SARS-CoV requires proteolytic processing of the replicase polyprotein by two viral cysteine proteases, a chymotrypsin-like protease (3CLpro) and a papain-like protease (PLpro). These proteases are important targets for the development of antiviral drugs. Protease inhibitors (especially nelfinavir) (386, 392), glycyrrhizin (77), baicalin (50), reserpine (381), aescin (381), valinomycin (381), niclosamide (380), aurintricarboxylic acid (129), mizoribine (293), indomethacin (4), chloroquine (174), and many herbal formulations, have also been found to possess some antiviral activity against SARS-CoV in vitro. In addition, an organic nitric oxide donor, S-nitro-N-acetylpenicillamine, appeared to have inhibitory activity against SARS-CoV (2), which has formed the basis for the use of nitric oxide inhalation as an experimental form of rescue therapy for SARS (52). Several agents with good in vitro antiviral activities, including ACE2 analogues, helicase inhibitors, and nucleoside analogues, were also reported to have some activity in vitro (14, 332). Antiviral peptides designed against the S protein and especially those derived from heptad repeat region 2 of S2 were shown to inhibit membrane fusion and cell entry (22, 177, 227). Small interfering RNA (siRNA) also demonstrated activities in reducing cytopathic effects, viral replication, and viral protein expression in cell lines (125, 232, 351, 418, 419, 428). Screening of chemical libraries has identified several inhibitors of protease, helicase, and spike-mediated cell entry (170). Most of the above-mentioned chemicals or approaches have not been evaluated in human or animal models. In mouse models, nelfinavir, β-d-N4-hydroxycytidine, calpain inhibitor VI, 3-deazaneplanocin A, human leukocyte IFN-αn3, and anti-inflammatory agents including chloroquine, amodiaquin, and pentoxifylline did not significantly reduce lung virus titers in mice. When not given in combination with other antivirals, the IMP dehydrogenase inhibitors, including ribavirin, suppress the proinflammatory response while augmenting viral replication in this mouse model (13).

View this table:
TABLE 8.

Antiviral agents and immunomodulators tested against SARS-CoV in animals and in vitro

Before the demonstration of viral load as an important factor in determining clinical outcome, immunomodulators were empirically used for the treatment of SARS during the initial epidemic (59). These immunomodulators include corticosteroids, intravenous immunoglobulins, pentaglobulin, thymosin, thalidomide, and anti-TNF (140, 421). Corticosteroids were previously found to reduce mortality in patients with pneumonia due to varicella-zoster virus and influenza virus (1, 109). High-dose hydrocortisone was shown to reduce the expression of the proinflammatory chemokines CXCL8 and CXCL10 in infected Caco-2 cells (80). However, without an effective antiviral agent, the early use of high doses of corticosteroids for prolonged periods could be detrimental. It may increase the plasma viral load and the risk of nosocomial infections and avascular osteonecrosis (196). Pegylated IFN-α2a was shown to be useful for prophylaxis and reducing respiratory viral shedding and lung pathology when used as an early treatment in a monkey model (118). Among clinical treatments studied, combinations of steroid with either alfacon-1, a recombinant consensus IFN-α (231), or protease inhibitors and ribavirin were found to improve outcomes in two different treatment trials using historical controls (33, 72). Due to the very short time course of this epidemic and the initial lack of suitable animal models, randomized control treatment trials are difficult to be organized and executed despite the finding of some commercially available candidate agents that appeared to be active in vitro.

INFECTION CONTROL AND LABORATORY SAFETY

Because of the physical stability of SARS-CoV in the environment, the absence of protective immunity in the general population, and the lack of effective antivirals or vaccines, infection control against SARS remains the primary means to prevent person-to-person transmission in future epidemics. Early recognition, triage, and prompt isolation of suspected cases are the principal measures against nosocomial transmission (142). Although respiratory droplet and contact precautions are effective under most circumstances (296), airborne precautions should be considered for aerosol-generating procedures such as bronchoscopy, tracheostomy, and suctioning of the airway. The virus can be easily inactivated by commonly used disinfectants such as household bleach, which reduced the viral load by more than 3 logs within 5 min (185). In a study on the survival of SARS-CoV, fecal and respiratory samples were shown to be infectious for 4 and >7 days at room temperature, respectively. Survival was found to be longer on disposable gowns than on cotton gowns. Therefore, absorbent material such as cotton is preferred over nonabsorptive material for personal protective clothing in routine patient care. In contrast, the virus cannot be recovered after the drying of a paper request form even with a high inoculum. Therefore, the risk of infection via contact with droplet-contaminated paper is small (185). When managing patients, oxygen delivery by low-flow nasal cannula instead of high-flow face masks should be used to reduce the risk of airborne transmission. Mechanical ventilation, including noninvasive modalities such as continuous positive airway pressure and bilevel positive airway pressure, should be carried out only in negative-pressure isolation rooms under strict airborne precautions (62). All health care personnel caring for patients with suspected or confirmed SARS must have daily temperature checks in the late afternoon and be quarantined after unprotected exposure to achieve early detection and to avoid nosocomial and community outbreaks. Upon discharge of patients, adherence to strict personal hygiene is important. Clinical specimens of patients remained RT-PCR positive for a substantial period of time, although the clinical significance of this finding is unknown (73). At the community level, contact tracing and quarantine of contacts, temperature checks at borders, health declarations for travelers, social distancing by suspension of schools and closing of workplaces, public education, and effective communication of information have been used to control community spread. Although screening of suspected cases at international borders and airports was widely practiced during the epidemic, the value of doing so has been questioned (307). To prevent laboratory-acquired infections, all laboratories handling live SARS-CoV should strictly comply with WHO standards for biosafety level 3 laboratories.

PASSIVE IMMUNIZATION AND DEVELOPMENT OF A SARS-CoV VACCINE

Use of Convalescent-Phase Serum and Neutralizing AntibodyPassive immunization using convalescent plasma with high titers of neutralizing antibody has been used for SARS patients who continued to deteriorate. No significant adverse reactions were noted, with perhaps some clinical benefit in a retrospective analysis (60, 401). Currently, only hyperimmune globulin produced from plasma from convalescent patients and equine plasma produced by immunization with inactivated SARS-CoV are available for prophylactic trials in humans (233, 421). A human monoclonal IgG1 produced from a single-chain variable region fragment against the S1 domain from two nonimmune human antibody libraries has also been produced (312). One of the single-chain variable region fragments, 80R, blocks spike-ACE2 receptor interactions through binding to the S1 domain. In a murine model of asymptomatic SARS infection, passive immunization by high titers of neutralizing antibody prevented viral replication in the lungs but was not as effective in nasal turbinates (311). Similarly, passive immunization of mice and ferrets with human IgG1 monoclonal antibody CR3014 was effective in preventing the development of lung pathology but less effective in reducing pharyngeal excretion (329). Recently, potent cross-reactive monoclonal antibodies against highly conserved sites within the spike protein, which can neutralize zoonotic or epidemic SARS-CoV, were reported (131, 434). These new weapons should be considered for clinical testing if SARS returns. Currently, there are no randomized placebo-controlled trials on the role of antibody therapy for pre- or postexposure prophylaxis in at-risk groups during the SARS epidemic.

Of all the surface proteins, only the ectodomains of S and Orf3a can induce significant neutralizing antibody with some augmentation from the M and E proteins (3, 24). The S1 fragment between amino acids 318 and 510 is the receptor binding domain for ACE2. This fragment induces the majority of the neutralizing antibody in convalescent SARS patients (135). The minor epitope for the neutralizing antibody is found at amino acids 1055 to 1192 around heptad repeat 2 of the S2 subunit. However, this minor neutralizing epitope was implicated in the induction of an infection-enhancing antibody (400). The risk of immune enhancement should not be underestimated because ferrets immunized by whole S protein carried in modified vaccinia virus Ankara developed hepatitis (355). Most of the highly immunodominant sites in S generate only nonneutralizing antibodies. It is important that only three to five amino acid changes in the receptor binding domain of S are found between the early and late isolates of human SARS (64), and even reverse-genetically-made isogenic viruses made with the spike protein from zoonotic variants and the early but not the late phase of the SARS epidemic can produce fatal disease in 1-year-old mice (289). Therefore, the receptor binding domain of S1 remains the best target for the development of a vaccine.

Active ImmunizationAs expected, the importance of the S protein was confirmed in the murine model using either intramuscular or intranasal administration of highly attenuated modified vaccinia virus Ankara carrying the S protein (18). Mucosal immunization of African green monkeys with recombinant attenuated parainfluenza virus-SARS-CoV S protein chimeric virus resulted in a good neutralizing antibody response and protection from viral replication in the upper and lower respiratory tracts following live SARS-CoV challenge (25). Other approaches to active immunization involved the use of an adenoviral vector carrying the S, M, and N proteins in rhesus macaques (102); subunit vaccine with S fragments in rabbits and mice (415); other vaccines derived from the SARS-CoV genome using reverse genetics, such as the attenuated rabies vector (94)-, attenuated vesicular stomatitis virus (171)-, or Venezuelan equine encephalitis virus (12, 85)-based vaccines; and S1 vaccine expressed in tomato and low-nicotine tobacco plants as a mucosal vaccine (262). A plasmid DNA vaccine carrying the S protein encoded by humanized codons was highly protective in a mouse model (412). The use of other targets such as inactivated whole virus in mice (323), DNA vaccine linking the N protein to calreticulin (176), DNA vaccination with the N gene in mice (433), and virus-like particles has also been reported. Only the inactivated whole-virus vaccine was tested in healthy Chinese volunteers, who showed good neutralizing antibodies with little side effects, but the data have not been published. However, the protective efficacy and risk of immune enhancement are still unknown in the situation of an epidemic.

As for the key protective immune effector in the mouse model, T-cell depletion with specific monoclonal antibodies against CD4 or CD8, alone or in combination with CD90, did not affect protective immunity, which was confirmed by adoptive T-cell transfer (399). Donor T cells alone did not inhibit pulmonary viral replication in recipient mice, whereas passive transfer of purified IgG from immunized mice achieved similar protection. In summary (Table 9), all vaccines based on the S protein appeared to be capable of inducing neutralizing antibody responses, and those based on nucleoprotein can induce nucleoprotein-specific cell-mediated immunity. However, only vaccines based on the S protein were shown to be protective in animal models, whereas a DNA vaccine based on the N protein induced immunopathology of lungs in mice after challenge with live virus (85).

View this table:
TABLE 9.

Passive and active immunization against SARS

The relative importance of systemic or mucosal immunity in terms of the neutralizing antibody or cytotoxic T-lymphocyte response against S, N, or other targets in terms of recovery from SARS is unknown. Nevertheless, neutralizing antibody against S1 appears to be crucial for prophylactic immunity. Live-attenuated virus is not a good choice because of the concern about reversion to virulence or recombination with wild strains to form new wild types. An inactivated SARS-CoV strain is the easiest and most likely candidate for clinical trials if SARS returns. Irrespective of the approach to immunization, the phenomenon of immune enhancement of disease in feline peritonitis coronavirus infection is also a cause for concern in view of the immunopathology seen in immunized ferrets and mice after challenge with wild-type SARS-CoV.

ANIMAL MODELS AND ANIMALS SUSCEPTIBLE TO SARS-CoV

Reproducible and consistent animal models that mimic the clinical, viral load, and histopathological changes of SARS are essential for proving causation, studying pathogenesis, and testing antivirals or immunization (Table 10). The Koch's postulates for SARS-CoV as a causative agent of SARS were fulfilled with a primate model using cynomolgus macaques (Macaca fascicularis), which demonstrated clinical and pathological features with some similarities to those found in humans (182). On the contrary, African green monkeys (Cercopithecus aethiops) did not develop significant lung pathology after inoculation with the SARS-CoV. The lack of consistency in primate animal models of rhesus, cynomolgus, and African green monkeys for experimental SARS was noted in another study (239). Moreover, these large mammals are expensive and difficult to handle. BALB/c mice demonstrated asymptomatic or mild infections in lungs and nasal turbinates by intranasal inoculation, which was not significantly different from the findings with inoculation of immunological Th1-biased C57BL/6 mice (105). BALB/c mice that were 12 to 14 months old developed symptomatic pneumonia, which correlated with the age-related susceptibility to acute SARS in humans (287). As expected, STAT-1 knockout-immunodeficient mice had fatal and disseminated disease (143). Transgenic mice expressing human ACE2 receptors also developed fatal disease, with extrapulmonary dissemination to many organs including the brain (240, 337). It is interesting that mouse-adapted SARS-CoV strains with six amino acid mutations can also cause fatal disseminated disease in young BALB/c mice (286). Adult F344 rats developed symptomatic disease after inoculation with passaged SARS-CoV strains containing one mutation in the receptor binding domain of S (244). Ferrets (Mustela furo) and domestic cats (Felis domesticus) were also susceptible to infection by SARS-CoV (237). The cats remained asymptomatic, and only some of the infected ferrets died of the disease. Very high levels of viral replication were found in infected golden Syrian hamsters, but they generally did not develop overt clinical disease (288). Similarly, inoculated common marmosets generally had mild clinical disease and histopathological changes of pneumonia with extrapulmonary dissemination and high levels of viral replication in affected tissues (111). As expected, palm civets (Paguma larvata) were shown to be susceptible to symptomatic infection by SARS-CoV with or without the 29-bp signature sequence (382). Pigs and chickens are not susceptible to SARS-CoV (356). Since different SARS-CoV isolates were used by different groups, it is therefore still uncertain whether one particular animal would be better than others as a model for SARS-CoV. It appears that the senescent BALB/c mouse is an inexpensive and relatively easily reproduced animal model for testing vaccines and antivirals for SARS. An important observation of this review is the diverse range of mammalian species that are susceptible to experimental infection by SARS-CoV, which again demonstrated that SARS-CoV is highly capable of jumping interspecies barriers and is an excellent candidate as an emerging or reemerging pathogen. Indeed, our first report on animal SARS-CoV showed that Chinese ferret badgers (Melogale moschata) and raccoon dogs (Nyctereutes procyonoides) were also infected with SARS-CoV (117). The recent discovery of a high proportion of Chinese horseshoe bats and subsequently other horseshoe bats shedding SARS-CoV-like viruses or being seropositive strongly suggested that the bats could be the natural reservoir of this group of viruses (190, 215).

View this table:
TABLE 10.

Animals tested for susceptibility to SARS-CoV in experimental and natural infectiona

SHOULD WE BE READY FOR THE REEMERGENCE OF SARS?

The medical and scientific community demonstrated marvelous efforts in the understanding and control of SARS within a short time, as evident by over 4,000 publications available online. Despite these achievements, gaps still exist in terms of the molecular basis of the physical stability and transmissibility of this virus, the molecular and immunological basis of disease pathogenesis in humans, screening tests for early or cryptic SARS cases, foolproof infection control procedures for patient care, effective antivirals or antiviral combinations, the usefulness of immunomodulatory agents for late presenters, an effective vaccine with no immune enhancement, and the immediate animal host that transmitted the virus to caged civets in the market at the beginning of the epidemic. Coronaviruses are well known to undergo genetic recombination (375), which may lead to new genotypes and outbreaks. The presence of a large reservoir of SARS-CoV-like viruses in horseshoe bats, together with the culture of eating exotic mammals in southern China, is a time bomb. The possibility of the reemergence of SARS and other novel viruses from animals or laboratories and therefore the need for preparedness should not be ignored.

ACKNOWLEDGMENTS

This review is dedicated to the late Henry Fok for his generous support to the research on emerging infections.

We acknowledge research funding from Hui Hoy and Hui Ming, Richard Y. H. Yu and family, the HKU Special Research Achievement Award, and the Croucher Senior Medical Research Fellowship 2006-2007.

We also acknowledge the help of Huang Yi for her assistance in preparing the phylogenetic tree.

REFERENCES

  1. 1.↵
    Ahmed, R., Q. A. Ahmed, N. A. Adhami, and Z. A. Memish. 2002. Varicella pneumonia: another ‘steroid responsive’ pneumonia? J. Chemother.14:220-222.
    OpenUrlCrossRefPubMed
  2. 2.↵
    Akerstrom, S., M. Mousavi-Jazi, J. Klingstrom, M. Leijon, A. Lundkvist, and A. Mirazimi. 2005. Nitric oxide inhibits the replication cycle of severe acute respiratory syndrome coronavirus. J. Virol.79:1966-1969.
    OpenUrlAbstract/FREE Full Text
  3. 3.↵
    Akerstrom, S., Y. J. Tan, and A. Mirazimi. 2006. Amino acids 15-28 in the ectodomain of SARS coronavirus 3a protein induces neutralizing antibodies. FEBS Lett.580:3799-3803.
    OpenUrlCrossRefPubMed
  4. 4.↵
    Amici, C., A. Di Coro, A. Ciucci, L. Chiappa, C. Castilletti, V. Martella, N. Decaro, C. Buonavoglia, M. R. Capobianchi, and M. G. Santoro. 2006. Indomethacin has a potent antiviral activity against SARS coronavirus. Antivir. Ther.11:1021-1030.
    OpenUrlPubMedWeb of Science
  5. 5.↵
    Anand, K., J. Ziebuhr, P. Wadhwani, J. R. Mesters, and R. Hilgenfeld. 2003. Coronavirus main proteinase (3CLpro) structure: basis for design of anti-SARS drugs. Science300:1763-1767.
    OpenUrlAbstract/FREE Full Text
  6. 6.↵
    Antonio, G. E., C. G. Ooi, K. T. Wong, E. L. Tsui, J. S. Wong, A. N. Sy, J. Y. Hui, C. Y. Chan, H. Y. Huang, Y. F. Chan, T. P. Wong, L. L. Leong, J. C. Chan, and A. T. Ahuja. 2005. Radiographic-clinical correlation in severe acute respiratory syndrome: study of 1373 patients in Hong Kong. Radiology237:1081-1090.
    OpenUrlCrossRefPubMedWeb of Science
  7. 7.↵
    Avendano, M., P. Derkach, and S. Swan. 2003. Clinical course and management of SARS in health care workers in Toronto: a case series. CMAJ168:1649-1660.
    OpenUrlAbstract/FREE Full Text
  8. 8.
    Baas, T., J. K. Taubenberger, P. Y. Chong, P. Chui, and M. G. Katze. 2006. SARS-CoV virus-host interactions and comparative etiologies of acute respiratory distress syndrome as determined by transcriptional and cytokine profiling of formalin-fixed paraffin-embedded tissues. J. Interf. Cytok. Res.26:309-317.
    OpenUrlCrossRef
  9. 9.↵
    Babcock, G. J., D. J. Esshaki, W. D. Thomas, Jr., and D. M. Ambrosino. 2004. Amino acids 270 to 510 of the severe acute respiratory syndrome coronavirus spike protein are required for interaction with receptor. J. Virol.78:4552-4560.
    OpenUrlAbstract/FREE Full Text
  10. 10.
    Balzarini, J., E. Keyaerts, L. Vijgen, H. Egberink, E. De Clercq, M. Van Ranst, S. S. Printsevskaya, E. N. Olsufyeva, S. E. Solovieva, and M. N. Preobrazhenskaya. 2006. Inhibition of feline (FIPV) and human (SARS) coronavirus by semisynthetic derivatives of glycopeptide antibiotics. Antivir. Res.72:20-33.
    OpenUrlCrossRefPubMedWeb of Science
  11. 11.
    Balzarini, J., E. Keyaerts, L. Vijgen, F. Vandermeer, M. Stevens, E. De Clercq, H. Egberink, and M. Van Ranst. 2006. Pyridine N-oxide derivatives are inhibitory to the human SARS and feline infectious peritonitis coronavirus in cell culture. J. Antimicrob. Chemother.57:472-481.
    OpenUrlCrossRefPubMedWeb of Science
  12. 12.↵
    Baric, R. S., T. Sheahan, D. Deming, E. Donaldson, B. Yount, A. C. Sims, R. S. Roberts, M. Frieman, and B. Rockx. 2006. SARS coronavirus vaccine development. Adv. Exp. Med. Biol.581:553-560.
    OpenUrlPubMed
  13. 13.↵
    Barnard, D. L., C. W. Day, K. Bailey, M. Heiner, R. Montgomery, L. Lauridsen, P. K. Chan, and R. W. Sidwell. 2006. Evaluation of immunomodulators, interferons and known in vitro SARS-coV inhibitors for inhibition of SARS-coV replication in BALB/c mice. Antivir. Chem. Chemother.17:275-284.
    OpenUrlCrossRefPubMed
  14. 14.↵
    Barnard, D. L., V. D. Hubbard, J. Burton, D. F. Smee, J. D. Morrey, M. J. Otto, and R. W. Sidwell. 2004. Inhibition of severe acute respiratory syndrome-associated coronavirus (SARSCoV) by calpain inhibitors and beta-D-N4-hydroxycytidine. Antivir. Chem. Chemother.15:15-22.
    OpenUrlCrossRefPubMed
  15. 15.↵
    Barretto, N., D. Jukneliene, K. Ratia, Z. Chen, A. D. Mesecar, and S. C. Baker. 2005. The papain-like protease of severe acute respiratory syndrome coronavirus has deubiquitinating activity. J. Virol.79:15189-15198.
    OpenUrlAbstract/FREE Full Text
  16. 16.
    Beijing Group of National Research Project for SARS. 2003. Dynamic changes in blood cytokine levels as clinical indicators in severe acute respiratory syndrome. Chin. Med. J.116:1283-1287.
    OpenUrlPubMed
  17. 17.↵
    Bernini, A., O. Spiga, A. Ciutti, S. Chiellini, L. Bracci, X. Yan, B. Zheng, J. Huang, M. L. He, H. D. Song, P. Hao, G. Zhao, and N. Niccolai. 2004. Prediction of quaternary assembly of SARS coronavirus peplomer. Biochem. Biophys. Res. Commun.325:1210-1214.
    OpenUrlCrossRefPubMedWeb of Science
  18. 18.↵
    Bisht, H., A. Roberts, L. Vogel, A. Bukreyev, P. L. Collins, B. R. Murphy, K. Subbarao, and B. Moss. 2004. Severe acute respiratory syndrome coronavirus spike protein expressed by attenuated vaccinia virus protectively immunizes mice. Proc. Natl. Acad. Sci. USA101:6641-6646.
    OpenUrlAbstract/FREE Full Text
  19. 19.
    Bisht, H., A. Roberts, L. Vogel, K. Subbarao, and B. Moss. 2005. Neutralizing antibody and protective immunity to SARS coronavirus infection of mice induced by a soluble recombinant polypeptide containing an N-terminal segment of the spike glycoprotein. Virology334:160-165.
    OpenUrlCrossRefPubMed
  20. 20.↵
    Bitnun, A., U. Allen, H. Heurter, S. M. King, M. A. Opavsky, E. L. Ford-Jones, A. Matlow, I. Kitai, R. Tellier, S. Richardson, D. Manson, P. Babyn, and S. Read. 2003. Children hospitalized with severe acute respiratory syndrome-related illness in Toronto. Pediatrics112:e261.
    OpenUrlAbstract/FREE Full Text
  21. 21.↵
    Booth, C. M., L. M. Matukas, G. A. Tomlinson, A. R. Rachlis, D. B. Rose, H. A. Dwosh, S. L. Walmsley, T. Mazzulli, M. Avendano, P. Derkach, I. E. Ephtimios, I. Kitai, B. D. Mederski, S. B. Shadowitz, W. L. Gold, L. A. Hawryluck, E. Rea, J. S. Chenkin, D. W. Cescon, S. M. Poutanen, and A. S. Detsky. 2003. Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area. JAMA289:2801-2809.
    OpenUrlCrossRefPubMedWeb of Science
  22. 22.↵
    Bosch, B. J., B. E. Martina, R. Van Der Zee, J. Lepault, B. J. Haijema, C. Versluis, A. J. Heck, R. De Groot, A. D. Osterhaus, and P. J. Rottier. 2004. Severe acute respiratory syndrome coronavirus (SARS-CoV) infection inhibition using spike protein heptad repeat-derived peptides. Proc. Natl. Acad. Sci. USA101:8455-8460.
    OpenUrlAbstract/FREE Full Text
  23. 23.↵
    Breugelmans, J. G., P. Zucs, K. Porten, S. Broll, M. Niedrig, A. Ammon, and G. Krause. 2004. SARS transmission and commercial aircraft. Emerg. Infect. Dis.10:1502-1503.
    OpenUrlCrossRefPubMedWeb of Science
  24. 24.↵
    Buchholz, U. J., A. Bukreyev, L. Yang, E. W. Lamirande, B. R. Murphy, K. Subbarao, and P. L. Collins. 2004. Contributions of the structural proteins of severe acute respiratory syndrome coronavirus to protective immunity. Proc. Natl. Acad. Sci. USA101:9804-9809.
    OpenUrlAbstract/FREE Full Text
  25. 25.↵
    Bukreyev, A., E. W. Lamirande, U. J. Buchholz, L. N. Vogel, W. R. Elkins, M. St. Claire, B. R. Murphy, K. Subbarao, and P. L. Collins. 2004. Mucosal immunisation of African green monkeys (Cercopithecus aethiops) with an attenuated parainfluenza virus expressing the SARS coronavirus spike protein for the prevention of SARS. Lancet363:2122-2127.
    OpenUrlCrossRefPubMedWeb of Science
  26. 26.↵
    Cameron, M. J., L. Ran, L. Xu, A. Danesh, J. F. Bermejo-Martin, C. M. Cameron, M. P. Muller, W. L. Gold, S. E. Richardson, S. M. Poutanen, B. M. Willey, M. E. Devries, Y. Fang, C. Seneviratne, S. E. Bosinger, D. Persad, P. Wilkinson, L. D. Greller, R. Somogyi, A. Humar, S. Keshavjee, M. Louie, M. B. Loeb, J. Brunton, A. J. McGeer, and D. J. Kelvin. 2007. Interferon-mediated immunopathological events are associated with atypical innate and adaptive immune responses in patients with severe acute respiratory syndrome. J. Virol.81:8692-8706.
    OpenUrlAbstract/FREE Full Text
  27. 27.
    Centers for Disease Control and Prevention. 2003. Outbreak of severe acute respiratory syndrome—worldwide, 2003. Morb. Mortal. Wkly. Rep.52:226-228.
    OpenUrlPubMed
  28. 28.↵
    Centers for Disease Control and Prevention. 2003. Prevalence of IgG antibody to SARS-associated coronavirus in animal traders—Guangdong Province, China, 2003. Morb. Mortal. Wkly. Rep.52:986-987.
    OpenUrlPubMed
  29. 29.
    Chan, C. M., C. W. Ma, W. Y. Chan, and H. Y. Chan. 2007. The SARS-coronavirus membrane protein induces apoptosis through modulating the Akt survival pathway. Arch. Biochem. Biophys.459:197-207.
    OpenUrlCrossRefPubMed
  30. 30.
    Chan, C. P., K. L. Siu, K. T. Chin, K. Y. Yuen, B. Zheng, and D. Y. Jin. 2006. Modulation of the unfolded protein response by the severe acute respiratory syndrome coronavirus spike protein. J. Virol.80:9279-9287.
    OpenUrlAbstract/FREE Full Text
  31. 31.↵
    Chan, K. H., V. C. Cheng, P. C. Woo, S. K. Lau, L. L. Poon, Y. Guan, W. H. Seto, K. Y. Yuen, and J. S. Peiris. 2005. Serological responses in patients with severe acute respiratory syndrome coronavirus infection and cross-reactivity with human coronaviruses 229E, OC43, and NL63. Clin. Diagn. Lab. Immunol.12:1317-1321.
    OpenUrlCrossRefPubMed
  32. 32.↵
    Chan, K. H., L. L. Poon, V. C. Cheng, Y. Guan, I. F. Hung, J. Kong, L. Y. Yam, W. H. Seto, K. Y. Yuen, and J. S. Peiris. 2004. Detection of SARS coronavirus in patients with suspected SARS. Emerg. Infect. Dis.10:294-299.
    OpenUrlCrossRefPubMedWeb of Science
  33. 33.↵
    Chan, K. S., S. T. Lai, C. M. Chu, E. Tsui, C. Y. Tam, M. M. Wong, M. W. Tse, T. L. Que, J. S. Peiris, J. Sung, V. C. Wong, and K. Y. Yuen. 2003. Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study. Hong Kong Med. J.9:399-406.
    OpenUrlPubMed
  34. 34.↵
    Chan, K. S., J. P. Zheng, Y. W. Mok, Y. M. Li, Y. N. Liu, C. M. Chu, and M. S. Ip. 2003. SARS: prognosis, outcome and sequelae. Respirology8:S36-S40.
    OpenUrlCrossRefPubMedWeb of Science
  35. 35.↵
    Chan, K. Y., J. C. Ching, M. S. Xu, A. N. Cheung, S. P. Yip, L. Y. Yam, S. T. Lai, C. M. Chu, A. T. Wong, Y. Q. Song, F. P. Huang, W. Liu, P. H. Chung, G. M. Leung, E. Y. Chow, E. Y. Chan, J. C. Chan, H. Y. Ngan, P. Tam, L. C. Chan, P. Sham, V. S. Chan, M. Peiris, S. C. Lin, and U. S. Khoo. 2007. Association of ICAM3 genetic variant with severe acute respiratory syndrome. J. Infect. Dis.196:271-280.
    OpenUrlCrossRefPubMedWeb of Science
  36. 36.↵
    Chan, M. H., P. K. Chan, J. F. Griffith, I. H. Chan, L. C. Lit, C. K. Wong, G. E. Antonio, E. Y. Liu, D. S. Hui, M. W. Suen, A. T. Ahuja, J. J. Sung, and C. W. Lam. 2006. Steroid-induced osteonecrosis in severe acute respiratory syndrome: a retrospective analysis of biochemical markers of bone metabolism and corticosteroid therapy. Pathology38:229-235.
    OpenUrlCrossRefPubMedWeb of Science
  37. 37.↵
    Chan, P. K., M. Ip, K. C. Ng, C. W. Rickjason, A. Wu, N. Lee, T. H. Rainer, G. M. Joynt, J. J. Sung, and J. S. Tam. 2003. Severe acute respiratory syndrome-associated coronavirus infection. Emerg. Infect. Dis.9:1453-1454.
    OpenUrlCrossRefPubMedWeb of Science
  38. 38.
    Chan, P. K., K. C. Ng, R. C. Chan, R. K. Lam, V. C. Chow, M. Hui, A. Wu, N. Lee, F. H. Yap, F. W. Cheng, J. J. Sung, and J. S. Tam. 2004. Immunofluorescence assay for serologic diagnosis of SARS. Emerg. Infect. Dis.10:530-532.
    OpenUrlCrossRefPubMedWeb of Science
  39. 39.
    Chan, P. K., W. K. To, K. C. Ng, R. K. Lam, T. K. Ng, R. C. Chan, A. Wu, W. C. Yu, N. Lee, D. S. Hui, S. T. Lai, E. K. Hon, C. K. Li, J. J. Sung, and J. S. Tam. 2004. Laboratory diagnosis of SARS. Emerg. Infect. Dis.10:825-831.
    OpenUrlCrossRefPubMedWeb of Science
  40. 40.↵
    Chan, V. S., K. Y. Chan, Y. Chen, L. L. Poon, A. N. Cheung, B. Zheng, K. H. Chan, W. Mak, H. Y. Ngan, X. Xu, G. Screaton, P. K. Tam, J. M. Austyn, L. C. Chan, S. P. Yip, M. Peiris, U. S. Khoo, and C. L. Lin. 2006. Homozygous L-SIGN (CLEC4M) plays a protective role in SARS coronavirus infection. Nat. Genet.38:38-46.
    OpenUrlCrossRefPubMedWeb of Science
  41. 41.↵
    Chan, W. M., Y. W. Kwan, H. S. Wan, C. W. Leung, and M. C. Chiu. 2004. Epidemiologic linkage and public health implication of a cluster of severe acute respiratory syndrome in an extended family. Pediatr. Infect. Dis. J.23:1156-1159.
    OpenUrlPubMed
  42. 42.↵
    Chan, W. M., K. S. Yuen, D. S. Fan, D. S. Lam, P. K. Chan, and J. J. Sung. 2004. Tears and conjunctival scrapings for coronavirus in patients with SARS. Br. J. Ophthalmol.88:968-969.
    OpenUrlFREE Full Text
  43. 43.↵
    Chang, Y. J., C. Y. Liu, B. L. Chiang, Y. C. Chao, and C. C. Chen. 2004. Induction of IL-8 release in lung cells via activator protein-1 by recombinant baculovirus displaying severe acute respiratory syndrome-coronavirus spike proteins: identification of two functional regions. J. Immunol.173:7602-7614.
    OpenUrlAbstract/FREE Full Text
  44. 44.↵
    Chau, T. N., K. C. Lee, H. Yao, T. Y. Tsang, T. C. Chow, Y. C. Yeung, K. W. Choi, Y. K. Tso, T. Lau, S. T. Lai, and C. L. Lai. 2004. SARS-associated viral hepatitis caused by a novel coronavirus: report of three cases. Hepatology39:302-310.
    OpenUrlCrossRefPubMed
  45. 45.↵
    Che, X. Y., B. Di, G. P. Zhao, Y. D. Wang, L. W. Qiu, W. Hao, M. Wang, P. Z. Qin, Y. F. Liu, K. H. Chan, V. C. Cheng, and K. Y. Yuen. 2006. A patient with asymptomatic severe acute respiratory syndrome (SARS) and antigenemia from the 2003-2004 community outbreak of SARS in Guangzhou, China. Clin. Infect. Dis.43:e1-e5.
    OpenUrlCrossRefPubMed
  46. 46.↵
    Che, X. Y., W. Hao, Y. Wang, B. Di, K. Yin, Y. C. Xu, C. S. Feng, Z. Y. Wan, V. C. Cheng, and K. Y. Yuen. 2004. Nucleocapsid protein as early diagnostic marker for SARS. Emerg. Infect. Dis.10:1947-1949.
    OpenUrlPubMedWeb of Science
  47. 47.↵
    Che, X. Y., L. W. Qiu, Z. Y. Liao, Y. D. Wang, K. Wen, Y. X. Pan, W. Hao, Y. B. Mei, V. C. Cheng, and K. Y. Yuen. 2005. Antigenic cross-reactivity between severe acute respiratory syndrome-associated coronavirus and human coronaviruses 229E and OC43. J. Infect. Dis.191:2033-2037.
    OpenUrlCrossRefPubMed
  48. 48.
    Che, X. Y., L. W. Qiu, Y. X. Pan, K. Wen, W. Hao, L. Y. Zhang, Y. D. Wang, Z. Y. Liao, X. Hua, V. C. Cheng, and K. Y. Yuen. 2004. Sensitive and specific monoclonal antibody-based capture enzyme immunoassay for detection of nucleocapsid antigen in sera from patients with severe acute respiratory syndrome. J. Clin. Microbiol.42:2629-2635.
    OpenUrlAbstract/FREE Full Text
  49. 49.
    Chen, C. Y., Y. H. Ping, H. C. Lee, K. H. Chen, Y. M. Lee, Y. J. Chan, T. C. Lien, T. S. Jap, C. H. Lin, L. S. Kao, and Y. M. Chen. 2007. Open reading frame 8a of the human severe acute respiratory syndrome coronavirus not only promotes viral replication but also induces apoptosis. J. Infect. Dis.196:405-415.
    OpenUrlCrossRefPubMed
  50. 50.↵
    Chen, F., K. H. Chan, Y. Jiang, R. Y. Kao, H. T. Lu, K. W. Fan, V. C. Cheng, W. H. Tsui, I. F. Hung, T. S. Lee, Y. Guan, J. S. Peiris, and K. Y. Yuen. 2004. In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds. J. Clin. Virol.31:69-75.
    OpenUrlPubMedWeb of Science
  51. 51.
    Chen, L., C. Gui, X. Luo, Q. Yang, S. Gunther, E. Scandella, C. Drosten, D. Bai, X. He, B. Ludewig, J. Chen, H. Luo, Y. Yang, Y. Yang, J. Zou, V. Thiel, K. Chen, J. Shen, X. Shen, and H. Jiang. 2005. Cinanserin is an inhibitor of the 3C-like proteinase of severe acute respiratory syndrome coronavirus and strongly reduces virus replication in vitro. J. Virol.79:7095-7103.
    OpenUrlAbstract/FREE Full Text
  52. 52.↵
    Chen, L., P. Liu, H. Gao, B. Sun, D. Chao, F. Wang, Y. Zhu, G. Hedenstierna, and C. G. Wang. 2004. Inhalation of nitric oxide in the treatment of severe acute respiratory syndrome: a rescue trial in Beijing. Clin. Infect. Dis.39:1531-1535.
    OpenUrlCrossRefPubMed
  53. 53.↵
    Chen, M. I., S. C. Loon, H. N. Leong, and Y. S. Leo. 2006. Understanding the super-spreading events of SARS in Singapore. Ann. Acad. Med. Singapore35:390-394.
    OpenUrlPubMed
  54. 54.
    Chen, S., D. Lu, M. Zhang, J. Che, Z. Yin, S. Zhang, W. Zhang, X. Bo, Y. Ding, and S. Wang. 2005. Double-antigen sandwich ELISA for detection of antibodies to SARS-associated coronavirus in human serum. Eur. J. Clin. Microbiol. Infect. Dis.24:549-553.
    OpenUrlCrossRefPubMed
  55. 55.
    Chen, Z., L. Zhang, C. Qin, L. Ba, C. E. Yi, F. Zhang, Q. Wei, T. He, W. Yu, J. Yu, H. Gao, X. Tu, A. Gettie, M. Farzan, K. Y. Yuen, and D. D. Ho. 2005. Recombinant modified vaccinia virus Ankara expressing the spike glycoprotein of severe acute respiratory syndrome coronavirus induces protective neutralizing antibodies primarily targeting the receptor binding region. J. Virol.79:2678-2688.
    OpenUrlAbstract/FREE Full Text
  56. 56.↵
    Cheng, P. K., D. A. Wong, L. K. Tong, S. M. Ip, A. C. Lo, C. S. Lau, E. Y. Yeung, and W. W. Lim. 2004. Viral shedding patterns of coronavirus in patients with probable severe acute respiratory syndrome. Lancet363:1699-1700.
    OpenUrlCrossRefPubMedWeb of Science
  57. 57.↵
    Cheng, S. K., C. W. Wong, J. Tsang, and K. C. Wong. 2004. Psychological distress and negative appraisals in survivors of severe acute respiratory syndrome (SARS). Psychol. Med.34:1187-1195.
    OpenUrlCrossRefPubMedWeb of Science
  58. 58.↵
    Cheng, V. C., I. F. Hung, B. S. Tang, C. M. Chu, M. M. Wong, K. H. Chan, A. K. Wu, D. M. Tse, K. S. Chan, B. J. Zheng, J. S. Peiris, J. J. Sung, and K. Y. Yuen. 2004. Viral replication in the nasopharynx is associated with diarrhea in patients with severe acute respiratory syndrome. Clin. Infect. Dis.38:467-475.
    OpenUrlCrossRefPubMedWeb of Science
  59. 59.↵
    Cheng, V. C., B. S. Tang, A. K. Wu, C. M. Chu, and K. Y. Yuen. 2004. Medical treatment of viral pneumonia including SARS in immunocompetent adult. J. Infect.49:262-273.
    OpenUrlCrossRefPubMedWeb of Science
  60. 60.↵
    Cheng, Y., R. Wong, Y. O. Soo, W. S. Wong, C. K. Lee, M. H. Ng, P. Chan, K. C. Wong, C. B. Leung, and G. Cheng. 2005. Use of convalescent plasma therapy in SARS patients in Hong Kong. Eur. J. Clin. Microbiol. Infect. Dis.24:44-46.
    OpenUrlCrossRefPubMedWeb of Science
  61. 61.↵
    Cheung, C. Y., L. L. Poon, I. H. Ng, W. Luk, S. F. Sia, M. H. Wu, K. H. Chan, K. Y. Yuen, S. Gordon, Y. Guan, and J. S. Peiris. 2005. Cytokine responses in severe acute respiratory syndrome coronavirus-infected macrophages in vitro: possible relevance to pathogenesis. J. Virol.79:7819-7826.
    OpenUrlAbstract/FREE Full Text
  62. 62.↵
    Cheung, T. M., L. Y. Yam, L. K. So, A. C. Lau, E. Poon, B. M. Kong, and R. W. Yung. 2004. Effectiveness of noninvasive positive pressure ventilation in the treatment of acute respiratory failure in severe acute respiratory syndrome. Chest126:845-850.
    OpenUrlCrossRefPubMedWeb of Science
  63. 63.↵
    Chien, J. Y., P. R. Hsueh, W. C. Cheng, C. J. Yu, and P. C. Yang. 2006. Temporal changes in cytokine/chemokine profiles and pulmonary involvement in severe acute respiratory syndrome. Respirology11:715-722.
    OpenUrlCrossRefPubMed
  64. 64.↵
    Chinese SARS Molecular Epidemiology Consortium. 2004. Molecular evolution of the SARS coronavirus during the course of the SARS epidemic in China. Science303:1666-1669.
    OpenUrlAbstract/FREE Full Text
  65. 65.
    Cho, J. H., D. L. Bernard, R. W. Sidwell, E. R. Kern, and C. K. Chu. 2006. Synthesis of cyclopentenyl carbocyclic nucleosides as potential antiviral agents against orthopoxviruses and SARS. J. Med. Chem.49:1140-1148.
    OpenUrlCrossRefPubMed
  66. 66.↵
    Chong, M. Y., W. C. Wang, W. C. Hsieh, C. Y. Lee, N. M. Chiu, W. C. Yeh, O. L. Huang, J. K. Wen, and C. L. Chen. 2004. Psychological impact of severe acute respiratory syndrome on health workers in a tertiary hospital. Br. J. Psych.185:127-133.
    OpenUrlAbstract/FREE Full Text
  67. 67.
    Chong, P. Y., P. Chui, A. E. Ling, T. J. Franks, D. Y. Tai, Y. S. Leo, G. J. Kaw, G. Wansaicheong, K. P. Chan, L. L. E. Oon, E. S. Teo, K. B. Tan, N. Nakajima, T. Sata, and W. D. Travis. 2004. Analysis of deaths during the severe acute respiratory syndrome (SARS) epidemic in Singapore: challenges in determining a SARS diagnosis. Arch. Pathol. Lab. Med.128:195-204.
    OpenUrlPubMedWeb of Science
  68. 68.↵
    Chow, K. Y., C. E. Lee, M. L. Ling, D. M. Heng, and S. G. Yap. 2004. Outbreak of severe acute respiratory syndrome in a tertiary hospital in Singapore, linked to an index patient with atypical presentation: epidemiological study. BMJ328:195.
    OpenUrlAbstract/FREE Full Text
  69. 69.↵
    Chow, P. K., E. E. Ooi, H. K. Tan, K. W. Ong, B. K. Sil, M. Teo, T. Ng, and K. C. Soo. 2004. Healthcare worker seroconversion in SARS outbreak. Emerg. Infect. Dis.10:249-250.
    OpenUrlPubMed
  70. 70.↵
    Christian, M. D., M. Loutfy, L. C. McDonald, K. F. Martinez, M. Ofner, T. Wong, T. Wallington, W. L. Gold, B. Mederski, K. Green, and D. E. Low. 2004. Possible SARS coronavirus transmission during cardiopulmonary resuscitation. Emerg. Infect. Dis.10:287-293.
    OpenUrlPubMedWeb of Science
  71. 71.↵
    Chu, C. M., V. C. Cheng, I. F. Hung, K. S. Chan, B. S. Tang, T. H. Tsang, K. H. Chan, and K. Y. Yuen. 2005. Viral load distribution in SARS outbreak. Emerg. Infect. Dis.11:1882-1886.
    OpenUrlCrossRefPubMedWeb of Science
  72. 72.↵
    Chu, C. M., V. C. Cheng, I. F. Hung, M. M. Wong, K. H. Chan, K. S. Chan, R. Y. Kao, L. L. Poon, C. L. Wong, Y. Guan, J. S. Peiris, and K. Y. Yuen. 2004. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax59:252-256.
    OpenUrlAbstract/FREE Full Text
  73. 73.↵
    Chu, C. M., W. S. Leung, V. C. Cheng, K. H. Chan, A. W. Lin, V. L. Chan, J. Y. Lam, K. S. Chan, and K. Y. Yuen. 2005. Duration of RT-PCR positivity in severe acute respiratory syndrome. Eur. Respir. J.25:12-14.
    OpenUrlAbstract/FREE Full Text
  74. 74.↵
    Chu, C. M., Y. Y. Leung, J. Y. Hui, I. F. Hung, V. L. Chan, W. S. Leung, K. I. Law, C. S. Chan, K. S. Chan, and K. Y. Yuen. 2004. Spontaneous pneumomediastinum in patients with severe acute respiratory syndrome. Eur. Respir. J.23:802-804.
    OpenUrlAbstract/FREE Full Text
  75. 75.↵
    Chu, C. M., L. L. Poon, V. C. Cheng, K. S. Chan, I. F. Hung, M. M. Wong, K. H. Chan, W. S. Leung, B. S. Tang, V. L. Chan, W. L. Ng, T. C. Sim, P. W. Ng, K. I. Law, D. M. Tse, J. S. Peiris, and K. Y. Yuen. 2004. Initial viral load and the outcomes of SARS. CMAJ171:1349-1352.
    OpenUrlAbstract/FREE Full Text
  76. 76.
    Chu, K. H., W. K. Tsang, C. S. Tang, M. F. Lam, F. M. Lai, K. F. To, K. S. Fung, H. L. Tang, W. W. Yan, H. W. Chan, T. S. Lai, K. L. Tong, and K. N. Lai. 2005. Acute renal impairment in coronavirus-associated severe acute respiratory syndrome. Kidney Int.67:698-705.
    OpenUrlCrossRefPubMedWeb of Science
  77. 77.↵
    Cinatl, J., B. Morgenstern, G. Bauer, P. Chandra, H. Rabenau, and H. W. Doerr. 2003. Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. Lancet361:2045-2046.
    OpenUrlCrossRefPubMedWeb of Science
  78. 78.↵
    Cinatl, J., B. Morgenstern, G. Bauer, P. Chandra, H. Rabenau, and H. W. Doerr. 2003. Treatment of SARS with human interferons. Lancet362:293-294.
    OpenUrlCrossRefPubMedWeb of Science
  79. 79.↵
    Cinatl, J., Jr., G. Hoever, B. Morgenstern, W. Preiser, J. U. Vogel, W. K. Hofmann, G. Bauer, M. Michaelis, H. F. Rabenau, and H. W. Doerr. 2004. Infection of cultured intestinal epithelial cells with severe acute respiratory syndrome coronavirus. Cell. Mol. Life Sci.61:2100-2112.
    OpenUrlPubMed
  80. 80.↵
    Cinatl, J., Jr., M. Michaelis, B. Morgenstern, and H. W. Doerr. 2005. High-dose hydrocortisone reduces expression of the pro-inflammatory chemokines CXCL8 and CXCL10 in SARS coronavirus-infected intestinal cells. Int. J. Mol. Med.15:323-327.
    OpenUrlPubMed
  81. 81.↵
    Connor, R. F., and R. L. Roper. 2007. Unique SARS-CoV protein nsp1: bioinformatics, biochemistry and potential effects on virulence. Trends Microbiol.15:51-53.
    OpenUrlCrossRefPubMed
  82. 82.↵
    Cui, W., Y. Fan, W. Wu, F. Zhang, J. Y. Wang, and A. P. Ni. 2003. Expression of lymphocytes and lymphocyte subsets in patients with severe acute respiratory syndrome. Clin. Infect. Dis.37:857-859.
    OpenUrlCrossRefPubMedWeb of Science
  83. 83.
    Dahl, H., A. Linde, and O. Strannegard. 2004. In vitro inhibition of SARS virus replication by human interferons. Scand. J. Infect. Dis.36:829-831.
    OpenUrlCrossRefPubMed
  84. 84.
    de Lang, A., A. D. Osterhaus, and B. L. Haagmans. 2006. Interferon-gamma and interleukin-4 downregulate expression of the SARS coronavirus receptor ACE2 in Vero E6 cells. Virology353:474-481.
    OpenUrlCrossRefPubMed
  85. 85.↵
    Deming, D., T. Sheahan, M. Heise, B. Yount, N. Davis, A. Sims, M. Suthar, J. Harkema, A. Whitmore, R. Pickles, A. West, E. Donaldson, K. Curtis, R. Johnston, and R. Baric. 2006. Vaccine efficacy in senescent mice challenged with recombinant SARS-CoV bearing epidemic and zoonotic spike variants. PLoS Med.3:e525.
    OpenUrlCrossRefPubMed
  86. 86.
    Di, B., W. Hao, Y. Gao, M. Wang, Y. D. Wang, L. W. Qiu, K. Wen, D. H. Zhou, X. W. Wu, E. J. Lu, Z. Y. Liao, Y. B. Mei, B. J. Zheng, and X. Y. Che. 2005. Monoclonal antibody-based antigen capture enzyme-linked immunosorbent assay reveals high sensitivity of the nucleocapsid protein in acute-phase sera of severe acute respiratory syndrome patients. Clin. Diagn. Lab. Immunol.12:135-140.
    OpenUrlCrossRefPubMed
  87. 87.↵
    Ding, Y., H. Wang, H. Shen, Z. Li, J. Geng, H. Han, J. Cai, X. Li, W. Kang, D. Weng, Y. Lu, D. Wu, L. He, and K. Yao. 2003. The clinical pathology of severe acute respiratory syndrome (SARS): a report from China. J. Pathol.200:282-289.
    OpenUrlCrossRefPubMedWeb of Science
  88. 88.↵
    Drosten, C., L. L. Chiu, M. Panning, H. N. Leong, W. Preiser, J. S. Tam, S. Gunther, S. Kramme, P. Emmerich, W. L. Ng, H. Schmitz, and E. S. Koay. 2004. Evaluation of advanced reverse transcription-PCR assays and an alternative PCR target region for detection of severe acute respiratory syndrome-associated coronavirus. J. Clin. Microbiol.42:2043-2047.
    OpenUrlAbstract/FREE Full Text
  89. 89.↵
    Drosten, C., S. Gunther, W. Preiser, S. van der Werf, H. R. Brodt, S. Becker, H. Rabenau, M. Panning, L. Kolesnikova, R. A. Fouchier, A. Berger, A. M. Burguiere, J. Cinatl, M. Eickmann, N. Escriou, K. Grywna, S. Kramme, J. C. Manuguerra, S. Muller, V. Rickerts, M. Sturmer, S. Vieth, H. D. Klenk, A. D. Osterhaus, H. Schmitz, and H. W. Doerr. 2003. Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N. Engl. J. Med.348:1967-1976.
    OpenUrlCrossRefPubMedWeb of Science
  90. 90.↵
    Du, L., R. Y. Kao, Y. Zhou, Y. He, G. Zhao, C. Wong, S. Jiang, K. Y. Yuen, D. Y. Jin, and B. J. Zheng. 2007. Cleavage of spike protein of SARS coronavirus by protease factor Xa is associated with viral infectivity. Biochem. Biophys. Res. Commun.359:174-179.
    OpenUrlCrossRefPubMedWeb of Science
  91. 91.↵
    Duan, S. M., X. S. Zhao, R. F. Wen, J. J. Huang, G. H. Pi, S. X. Zhang, J. Han, S. L. Bi, L. Ruan, and X. P. Dong. 2003. Stability of SARS coronavirus in human specimens and environment and its sensitivity to heating and UV irradiation. Biomed. Environ. Sci.16:246-255.
    OpenUrlPubMedWeb of Science
  92. 92.↵
    Egloff, M. P., F. Ferron, V. Campanacci, S. Longhi, C. Rancurel, H. Dutartre, E. J. Snijder, A. E. Gorbalenya, C. Cambillau, and B. Canard. 2004. The severe acute respiratory syndrome-coronavirus replicative protein nsp9 is a single-stranded RNA-binding subunit unique in the RNA virus world. Proc. Natl. Acad. Sci. USA101:3792-3796.
    OpenUrlAbstract/FREE Full Text
  93. 93.↵
    Eickmann, M., S. Becker, H. D. Klenk, H. W. Doerr, K. Stadler, S. Censini, S. Guidotti, V. Masignani, M. Scarselli, M. Mora, C. Donati, J. H. Han, H. C. Song, S. Abrignani, A. Covacci, and R. Rappuoli. 2003. Phylogeny of the SARS coronavirus. Science302:1504-1505.
    OpenUrl
  94. 94.↵
    Faber, M., E. W. Lamirande, A. Roberts, A. B. Rice, H. Koprowski, B. Dietzschold, and M. J. Schnell. 2005. A single immunization with a rhabdovirus-based vector expressing severe acute respiratory syndrome coronavirus (SARS-CoV) S protein results in the production of high levels of SARS-CoV-neutralizing antibodies. J. Gen. Virol.86:1435-1440.
    OpenUrlCrossRefPubMed
  95. 95.↵
    Fan, Z., K. Peng, X. Tan, B. Yin, X. Dong, F. Qiu, Y. Shen, H. Wang, J. Yuan, B. Qiang, and X. Peng. 2005. Molecular cloning, expression, and purification of SARS-CoV nsp13. Protein Expr. Purif.41:235-240.
    OpenUrlCrossRefPubMed
  96. 96.
    Farcas, G. A., S. M. Poutanen, T. Mazzulli, B. M. Willey, J. Butany, S. L. Asa, P. Faure, P. Akhavan, D. E. Low, and K. C. Kain. 2005. Fatal severe acute respiratory syndrome is associated with multiorgan involvement by coronavirus. J. Infect. Dis.191:193-197.
    OpenUrlCrossRefPubMedWeb of Science
  97. 97.↵
    Fielding, B. C., V. Gunalan, T. H. Tan, C. F. Chou, S. Shen, S. Khan, S. G. Lim, W. Hong, and Y. J. Tan. 2006. Severe acute respiratory syndrome coronavirus protein 7a interacts with hSGT. Biochem. Biophys. Res. Commun.343:1201-1208.
    OpenUrlCrossRefPubMed
  98. 98.
    Fouchier, R. A., T. Kuiken, M. Schutten, G. van Amerongen, G. J. van Doornum, B. G. van den Hoogen, M. Peiris, W. Lim, K. Stohr, and A. D. Osterhaus. 2003. Aetiology: Koch's postulates fulfilled for SARS virus. Nature423:240.
    OpenUrlCrossRefPubMedWeb of Science
  99. 99.↵
    Franks, T. J., P. Y. Chong, P. Chui, J. R. Galvin, R. M. Lourens, A. H. Reid, E. Selbs, C. P. McEvoy, C. D. Hayden, J. Fukuoka, J. K. Taubenberger, and W. D. Travis. 2003. Lung pathology of severe acute respiratory syndrome (SARS): a study of 8 autopsy cases from Singapore. Hum. Pathol.34:743-748.
    OpenUrlCrossRefPubMedWeb of Science
  100. 100.
    Frieman, M., B. Yount, M. Heise, S. A. Kopecky-Bromberg, P. Palese, and R. S. Baric. 2007. SARS-CoV ORF6 antagonizes STAT1 function by sequestering nuclear import factors on the rER/Golgi membrane. J. Virol.81:9812-9824.
    OpenUrlAbstract/FREE Full Text
  101. 101.
    Gan, Y. R., H. Huang, Y. D. Huang, C. M. Rao, Y. Zhao, J. S. Liu, L. Wu, and D. Q. Wei. 2006. Synthesis and activity of an octapeptide inhibitor designed for SARS coronavirus main proteinase. Peptides27:622-625.
    OpenUrlCrossRefPubMedWeb of Science
  102. 102.↵
    Gao, W., A. Tamin, A. Soloff, L. D'Aiuto, E. Nwanegbo, P. D. Robbins, W. J. Bellini, S. Barratt-Boyes, and A. Gambotto. 2003. Effects of a SARS-associated coronavirus vaccine in monkeys. Lancet362:1895-1896.
    OpenUrlCrossRefPubMedWeb of Science
  103. 103.
    Ghosh, A. K., K. Xi, K. Ratia, B. D. Santarsiero, W. Fu, B. H. Harcourt, P. A. Rota, S. C. Baker, M. E. Johnson, and A. D. Mesecar. 2005. Design and synthesis of peptidomimetic severe acute respiratory syndrome chymotrypsin-like protease inhibitors. J. Med. Chem.48:6767-6771.
    OpenUrlCrossRefPubMedWeb of Science
  104. 104.↵
    Gillim-Ross, L., J. Taylor, D. R. Scholl, J. Ridenour, P. S. Masters, and D. E. Wentworth. 2004. Discovery of novel human and animal cells infected by the severe acute respiratory syndrome coronavirus by replication-specific multiplex reverse transcription-PCR. J. Clin. Microbiol.42:3196-3206.
    OpenUrlAbstract/FREE Full Text
  105. 105.↵
    Glass, W. G., K. Subbarao, B. Murphy, and P. M. Murphy. 2004. Mechanisms of host defense following severe acute respiratory syndrome-coronavirus (SARS-CoV) pulmonary infection of mice. J. Immunol.173:4030-4039.
    OpenUrlAbstract/FREE Full Text
  106. 106.
    Graham, R. L., A. C. Sims, S. M. Brockway, R. S. Baric, and M. R. Denison. 2005. The nsp2 replicase proteins of murine hepatitis virus and severe acute respiratory syndrome coronavirus are dispensable for viral replication. J. Virol.79:13399-13411.
    OpenUrlAbstract/FREE Full Text
  107. 107.↵
    Gramberg, T., H. Hofmann, P. Moller, P. F. Lalor, A. Marzi, M. Geier, M. Krumbiegel, T. Winkler, F. Kirchhoff, D. H. Adams, S. Becker, J. Munch, and S. Pohlmann. 2005. LSECtin interacts with filovirus glycoproteins and the spike protein of SARS coronavirus. Virology340:224-236.
    OpenUrlCrossRefPubMedWeb of Science
  108. 108.↵
    Grant, P. R., J. A. Garson, R. S. Tedder, P. K. Chan, J. S. Tam, and J. J. Sung. 2003. Detection of SARS coronavirus in plasma by real-time RT-PCR. N. Engl. J. Med.349:2468-2469.
    OpenUrlCrossRefPubMedWeb of Science
  109. 109.↵
    Greaves, I. A., H. J. Colebatch, and T. A. Torda. 1981. A possible role for corticosteroids in the treatment of influenzal pneumonia. Aust. N. Z. J. Med.11:271-276.
    OpenUrlPubMed
  110. 110.
    Greenough, T. C., G. J. Babcock, A. Roberts, H. J. Hernandez, W. D. Thomas, Jr., J. A. Coccia, R. F. Graziano, M. Srinivasan, I. Lowy, R. W. Finberg, K. Subbarao, L. Vogel, M. Somasundaran, K. Luzuriaga, J. L. Sullivan, and D. M. Ambrosino. 2005. Development and characterization of a severe acute respiratory syndrome-associated coronavirus-neutralizing human monoclonal antibody that provides effective immunoprophylaxis in mice. J. Infect. Dis.191:507-514.
    OpenUrlCrossRefPubMedWeb of Science
  111. 111.↵
    Greenough, T. C., A. Carville, J. Coderre, M. Somasundaran, J. L. Sullivan, K. Luzuriaga, and K. Mansfield. 2005. Pneumonitis and multi-organ system disease in common marmosets (Callithrix jacchus) infected with the severe acute respiratory syndrome-associated coronavirus. Am. J. Pathol.167:455-463.
    OpenUrlCrossRefPubMedWeb of Science
  112. 112.↵
    Griffith, J. F., G. E. Antonio, S. M. Kumta, D. S. Hui, J. K. Wong, G. M. Joynt, A. K. Wu, A. Y. Cheung, K. H. Chiu, K. M. Chan, P. C. Leung, and A. T. Ahuja. 2005. Osteonecrosis of hip and knee in patients with severe acute respiratory syndrome treated with steroids. Radiology235:168-175.
    OpenUrlCrossRefPubMedWeb of Science
  113. 113.↵
    Grinblat, L., H. Shulman, A. Glickman, L. Matukas, and N. Paul. 2003. Severe acute respiratory syndrome: radiographic review of 40 probable cases in Toronto, Canada. Radiology228:802-809.
    OpenUrlPubMedWeb of Science
  114. 114.
    Guan, M., K. H. Chan, J. S. Peiris, S. W. Kwan, S. Y. Lam, C. M. Pang, K. W. Chu, K. M. Chan, H. Y. Chen, E. B. Phuah, and C. J. Wong. 2004. Evaluation and validation of an enzyme-linked immunosorbent assay and an immunochromatographic test for serological diagnosis of severe acute respiratory syndrome. Clin. Diagn. Lab. Immunol.11:699-703.
    OpenUrlCrossRefPubMed
  115. 115.
    Guan, M., H. Y. Chen, S. Y. Foo, Y. J. Tan, P. Y. Goh, and S. H. Wee. 2004. Recombinant protein-based enzyme-linked immunosorbent assay and immunochromatographic tests for detection of immunoglobulin G antibodies to severe acute respiratory syndrome (SARS) coronavirus in SARS patients. Clin. Diagn. Lab. Immunol.11:287-291.
    OpenUrlCrossRefPubMed
  116. 116.↵
    Guan, Y., J. S. Peiris, B. Zheng, L. L. Poon, K. H. Chan, F. Y. Zeng, C. W. Chan, M. N. Chan, J. D. Chen, K. Y. Chow, C. C. Hon, K. H. Hui, J. Li, V. Y. Li, Y. Wang, S. W. Leung, K. Y. Yuen, and F. C. Leung. 2004. Molecular epidemiology of the novel coronavirus that causes severe acute respiratory syndrome. Lancet363:99-104.
    OpenUrlCrossRefPubMedWeb of Science
  117. 117.↵
    Guan, Y., B. J. Zheng, Y. Q. He, X. L. Liu, Z. X. Zhuang, C. L. Cheung, S. W. Luo, P. H. Li, L. J. Zhang, Y. J. Guan, K. M. Butt, K. L. Wong, K. W. Chan, W. Lim, K. F. Shortridge, K. Y. Yuen, J. S. Peiris, and L. L. Poon. 2003. Isolation and characterization of viruses related to the SARS coronavirus from animals in southern China. Science302:276-278.
    OpenUrlAbstract/FREE Full Text
  118. 118.↵
    Haagmans, B. L., T. Kuiken, B. E. Martina, R. A. Fouchier, G. F. Rimmelzwaan, G. van Amerongen, D. van Riel, T. de Jong, S. Itamura, K. H. Chan, M. Tashiro, and A. D. Osterhaus. 2004. Pegylated interferon-alpha protects type 1 pneumocytes against SARS coronavirus infection in macaques. Nat. Med.10:290-293.
    OpenUrlCrossRefPubMedWeb of Science
  119. 119.↵
    Hamming, I., W. Timens, M. L. Bulthuis, A. T. Lely, G. J. Navis, and H. van Goor. 2004. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J. Pathol.203:631-637.
    OpenUrlCrossRefPubMedWeb of Science
  120. 120.
    Han, D. P., A. Penn-Nicholson, and M. W. Cho. 2006. Identification of critical determinants on ACE2 for SARS-CoV entry and development of a potent entry inhibitor. Virology350:15-25.
    OpenUrlCrossRefPubMed
  121. 121.↵
    Harcourt, B. H., D. Jukneliene, A. Kanjanahaluethai, J. Bechill, K. M. Severson, C. M. Smith, P. A. Rota, and S. C. Baker. 2004. Identification of severe acute respiratory syndrome coronavirus replicase products and characterization of papain-like protease activity. J. Virol.78:13600-13612.
    OpenUrlAbstract/FREE Full Text
  122. 122.↵
    Hattermann, K., M. A. Muller, A. Nitsche, S. Wendt, O. D. Mantke, and M. Niedrig. 2005. Susceptibility of different eukaryotic cell lines to SARS-coronavirus. Arch. Virol.150:1023-1031.
    OpenUrlCrossRefPubMed
  123. 123.
    He, H., Y. Tang, X. Qin, W. Xu, Y. Wang, X. Liu, X. Liu, S. Xiong, J. Li, M. Zhang, and M. Duan. 2005. Construction of a eukaryotic expression plasmid encoding partial S gene fragments of the SARS-CoV and its potential utility as a DNA vaccine. DNA Cell Biol.24:516-520.
    OpenUrlCrossRefPubMed
  124. 124.
    He, L., Y. Ding, Q. Zhang, X. Che, Y. He, H. Shen, H. Wang, Z. Li, L. Zhao, J. Geng, Y. Deng, L. Yang, J. Li, J. Cai, L. Qiu, K. Wen, X. Xu, and S. Jiang. 2006. Expression of elevated levels of pro-inflammatory cytokines in SARS-CoV-infected ACE2+ cells in SARS patients: relation to the acute lung injury and pathogenesis of SARS. J. Pathol.210:288-297.
    OpenUrlCrossRefPubMed
  125. 125.↵
    He, M. L., B. Zheng, Y. Peng, J. S. Peiris, L. L. Poon, K. Y. Yuen, M. C. Lin, H. F. Kung, and Y. Guan. 2003. Inhibition of SARS-associated coronavirus infection and replication by RNA interference. JAMA290:2665-2666.
    OpenUrlCrossRefPubMedWeb of Science
  126. 126.
    He, Q., K. H. Chong, H. H. Chng, B. Leung, A. E. Ling, T. Wei, S.-W. Chan, E. E. Ooi, and J. Kwang. 2004. Development of a Western blot assay for detection of antibodies against coronavirus causing severe acute respiratory syndrome. Clin. Diagn. Lab. Immunol.11:417-422.
    OpenUrlCrossRefPubMed
  127. 127.
    He, Q., Q. Du, S. Lau, I. Manopo, L. Lu, S. W. Chan, B. J. Fenner, and J. Kwang. 2005. Characterization of monoclonal antibody against SARS coronavirus nucleocapsid antigen and development of an antigen capture ELISA. J. Virol. Methods127:46-53.
    OpenUrlPubMedWeb of Science
  128. 128.↵
    He, Q., I. Manopo, L. Lu, B. P. Leung, H. H. Chng, A. E. Ling, L. L. Chee, S. W. Chan, E. E. Ooi, Y. L. Sin, B. Ang, and J. Kwang. 2005. Novel immunofluorescence assay using recombinant nucleocapsid-spike fusion protein as antigen to detect antibodies against severe acute respiratory syndrome coronavirus. Clin. Diagn. Lab. Immunol.12:321-328.
    OpenUrlCrossRefPubMed
  129. 129.↵
    He, R., A. Adonov, M. Traykova-Adonova, J. Cao, T. Cutts, E. Grudesky, Y. Deschambaul, J. Berry, M. Drebot, and X. Li. 2004. Potent and selective inhibition of SARS coronavirus replication by aurintricarboxylic acid. Biochem. Biophys. Res. Commun.320:1199-1203.
    OpenUrlCrossRefPubMedWeb of Science
  130. 130.
    He, R., A. Leeson, A. Andonov, Y. Li, N. Bastien, J. Cao, C. Osiowy, F. Dobie, T. Cutts, M. Ballantine, and X. Li. 2003. Activation of AP-1 signal transduction pathway by SARS coronavirus nucleocapsid protein. Biochem. Biophys. Res. Commun.311:870-876.
    OpenUrlCrossRefPubMedWeb of Science
  131. 131.↵
    He, Y., J. Li, W. Li, S. Lustigman, M. Farzan, and S. Jiang. 2006. Cross-neutralization of human and palm civet severe acute respiratory syndrome coronaviruses by antibodies targeting the receptor-binding domain of spike protein. J. Immunol.176:6085-6092.
    OpenUrlAbstract/FREE Full Text
  132. 132.
    He, Y., H. Lu, P. Siddiqui, Y. Zhou, and S. Jiang. 2005. Receptor-binding domain of severe acute respiratory syndrome coronavirus spike protein contains multiple conformation-dependent epitopes that induce highly potent neutralizing antibodies. J. Immunol.174:4908-4915.
    OpenUrlAbstract/FREE Full Text
  133. 133.
    He, Y., Y. Zhou, S. Liu, Z. Kou, W. Li, M. Farzan, and S. Jiang. 2004. Receptor-binding domain of SARS-CoV spike protein induces highly potent neutralizing antibodies: implication for developing subunit vaccine. Biochem. Biophys. Res. Commun.324:773-781.
    OpenUrlCrossRefPubMedWeb of Science
  134. 134.
    He, Y., Y. Zhou, P. Siddiqui, and S. Jiang. 2004. Inactivated SARS-CoV vaccine elicits high titers of spike protein-specific antibodies that block receptor binding and virus entry. Biochem. Biophys. Res. Commun.325:445-452.
    OpenUrlCrossRefPubMed
  135. 135.↵
    He, Y., Q. Zhu, S. Liu, Y. Zhou, B. Yang, J. Li, and S. Jiang. 2005. Identification of a critical neutralization determinant of severe acute respiratory syndrome (SARS)-associated coronavirus: importance for designing SARS vaccines. Virology334:74-82.
    OpenUrlCrossRefPubMedWeb of Science
  136. 136.
    He, Z., C. Zhao, Q. Dong, H. Zhuang, S. Song, G. Peng, and D. E. Dwyer. 2005. Effects of severe acute respiratory syndrome (SARS) coronavirus infection on peripheral blood lymphocytes and their subsets. Int. J. Infect. Dis.9:323-330.
    OpenUrlCrossRefPubMed
  137. 137.↵
    Hensley, L. E., L. E. Fritz, P. B. Jahrling, C. L. Karp, J. W. Huggins, and T. W. Geisbert. 2004. Interferon-beta 1a and SARS coronavirus replication. Emerg. Infect. Dis.10:317-319.
    OpenUrlCrossRefPubMedWeb of Science
  138. 138.↵
    Hiscox, J. A., D. Cavanagh, and P. Britton. 1995. Quantification of individual subgenomic mRNA species during replication of the coronavirus transmissible gastroenteritis virus. Virus Res.36:119-130.
    OpenUrlCrossRefPubMedWeb of Science
  139. 139.
    Ho, J. C., G. C. Ooi, T. Y. Mok, J. W. Chan, I. Hung, B. Lam, P. C. Wong, P. C. Li, P. L. Ho, W. K. Lam, C. K. Ng, M. S. Ip, K. N. Lai, M. Chan-Yeung, and K. W. Tsang. 2003. High-dose pulse versus nonpulse corticosteroid regimens in severe acute respiratory syndrome. Am. J. Respir. Crit. Care Med.168:1449-1456.
    OpenUrlCrossRefPubMedWeb of Science
  140. 140.↵
    Ho, J. C., A. Y. Wu, B. Lam, G. C. Ooi, P. L. Khong, P. L. Ho, M. Chan-Yeung, N. S. Zhong, C. Ko, W. K. Lam, and K. W. Tsang. 2004. Pentaglobin in steroid-resistant severe acute respiratory syndrome. Int. J. Tuberc. Lung Dis.8:1173-1179.
    OpenUrlPubMedWeb of Science
  141. 141.↵
    Ho, K. Y., K. S. Singh, A. G. Habib, B. K. Ong, T. K. Lim, E. E. Ooi, B. K. Sil, A. E. Ling, X. L. Bai, and P. A. Tambyah. 2004. Mild illness associated with severe acute respiratory syndrome coronavirus infection: lessons from a prospective seroepidemiologic study of health-care workers in a teaching hospital in Singapore. J. Infect. Dis.189:642-647.
    OpenUrlCrossRefPubMedWeb of Science
  142. 142.↵
    Ho, P. L., X. P. Tang, and W. H. Seto. 2003. SARS: hospital infection control and admission strategies. Respirology8:S41-S45.
    OpenUrlCrossRefPubMedWeb of Science
  143. 143.↵
    Hogan, R. J., G. Gao, T. Rowe, P. Bell, D. Flieder, J. Paragas, G. P. Kobinger, N. A. Wivel, R. G. Crystal, J. Boyer, H. Feldmann, T. G. Voss, and J. M. Wilson. 2004. Resolution of primary severe acute respiratory syndrome-associated coronavirus infection requires Stat1. J. Virol.78:11416-11421.
    OpenUrlAbstract/FREE Full Text
  144. 144.↵
    Hon, K. L., C. W. Leung, W. T. Cheng, P. K. Chan, W. C. Chu, Y. W. Kwan, A. M. Li, N. C. Fong, P. C. Ng, M. C. Chiu, C. K. Li, J. S. Tam, and T. F. Fok. 2003. Clinical presentations and outcome of severe acute respiratory syndrome in children. Lancet361:1701-1703.
    OpenUrlCrossRefPubMedWeb of Science
  145. 145.↵
    Hong, N., and X. K. Du. 2004. Avascular necrosis of bone in severe acute respiratory syndrome. Clin. Radiol.59:602-608.
    OpenUrlCrossRefPubMedWeb of Science
  146. 146.
    Hong, T. C., Q. L. Mai, D. V. Cuong, M. Parida, H. Minekawa, T. Notomi, F. Hasebe, and K. Morita. 2004. Development and evaluation of a novel loop-mediated isothermal amplification method for rapid detection of severe acute respiratory syndrome coronavirus. J. Clin. Microbiol.42:1956-1961.
    OpenUrlAbstract/FREE Full Text
  147. 147.↵
    Hsieh, P. K., S. C. Chang, C. C. Huang, T. T. Lee, C. W. Hsiao, Y. H. Kou, I. Y. Chen, C. K. Chang, T. H. Huang, and M. F. Chang. 2005. Assembly of severe acute respiratory syndrome coronavirus RNA packaging signal into virus-like particles is nucleocapsid dependent. J. Virol.79:13848-13855.
    OpenUrlAbstract/FREE Full Text
  148. 148.↵
    Hsieh, S. C., W. P. Chan, J. C. Chien, W. S. Lee, M. S. Yao, W. M. Choi, C. Y. Chen, and C. Yu. 2004. Radiographic appearance and clinical outcome correlates in 26 patients with severe acute respiratory syndrome. Am. J. Roentgenol.182:1119-1122.
    OpenUrlPubMedWeb of Science
  149. 149.↵
    Hsu, L. Y., C. C. Lee, J. A. Green, B. Ang, N. I. Paton, L. Lee, J. S. Villacian, P. L. Lim, A. Earnest, and Y. S. Leo. 2003. Severe acute respiratory syndrome (SARS) in Singapore: clinical features of index patient and initial contacts. Emerg. Infect. Dis.9:713-717.
    OpenUrlCrossRefPubMedWeb of Science
  150. 150.↵
    Huang, C., N. Ito, C. T. Tseng, and S. Makino. 2006. Severe acute respiratory syndrome coronavirus 7a accessory protein is a viral structural protein. J. Virol.80:7287-7294.
    OpenUrlAbstract/FREE Full Text
  151. 151.↵
    Huang, I. C., B. J. Bosch, F. Li, W. Li, K. H. Lee, S. Ghiran, N. Vasilieva, T. S. Dermody, S. C. Harrison, P. R. Dormitzer, M. Farzan, P. J. Rottier, and H. Choe. 2006. SARS coronavirus, but not human coronavirus NL63, utilizes cathepsin L to infect ACE2-expressing cells. J. Biol. Chem.281:3198-3203.
    OpenUrlAbstract/FREE Full Text
  152. 152.↵
    Huang, K. J., I. J. Su, M. Theron, Y. C. Wu, S. K. Lai, C. C. Liu, and H. Y. Lei. 2005. An interferon-gamma-related cytokine storm in SARS patients. J. Med. Virol.75:185-194.
    OpenUrlCrossRefPubMedWeb of Science
  153. 153.↵
    Hui, D. S., K. T. Wong, G. E. Antonio, N. Lee, A. Wu, V. Wong, W. Lau, J. C. Wu, L. S. Tam, L. M. Yu, G. M. Joynt, S. S. Chung, A. T. Ahuja, and J. J. Sung. 2004. Severe acute respiratory syndrome: correlation between clinical outcome and radiologic features. Radiology233:579-585.
    OpenUrlPubMedWeb of Science
  154. 154.↵
    Hui, D. S., K. T. Wong, F. W. Ko, L. S. Tam, D. P. Chan, J. Woo, and J. J. Sung. 2005. The 1-year impact of severe acute respiratory syndrome on pulmonary function, exercise capacity, and quality of life in a cohort of survivors. Chest128:2247-2261.
    OpenUrlCrossRefPubMedWeb of Science
  155. 155.↵
    Hui, R. K., F. Zeng, C. M. Chan, K. Y. Yuen, J. S. Peiris, and F. C. Leung. 2004. Reverse transcriptase PCR diagnostic assay for the coronavirus associated with severe acute respiratory syndrome. J. Clin. Microbiol.42:1994-1999.
    OpenUrlAbstract/FREE Full Text
  156. 156.↵
    Hung, I. F., V. C. Cheng, A. K. Wu, B. S. Tang, K. H. Chan, C. M. Chu, M. M. Wong, W. T. Hui, L. L. Poon, D. M. Tse, K. S. Chan, P. C. Woo, S. K. Lau, J. S. Peiris, and K. Y. Yuen. 2004. Viral loads in clinical specimens and SARS manifestations. Emerg. Infect. Dis.10:1550-1557.
    OpenUrlCrossRefPubMedWeb of Science
  157. 157.↵
    Hwang, D. M., D. W. Chamberlain, S. M. Poutanen, D. E. Low, S. L. Asa, and J. Butany. 2005. Pulmonary pathology of severe acute respiratory syndrome in Toronto. Mod. Pathol.18:1-10.
    OpenUrlCrossRefPubMedWeb of Science
  158. 158.↵
    Imbert, I., J. C. Guillemot, J. M. Bourhis, C. Bussetta, B. Coutard, M. P. Egloff, F. Ferron, A. E. Gorbalenya, and B. Canard. 2006. A second, non-canonical RNA-dependent RNA polymerase in SARS coronavirus. EMBO J.25:4933-4942.
    OpenUrlCrossRefPubMedWeb of Science
  159. 159.↵
    Ingallinella, P., E. Bianchi, M. Finotto, G. Cantoni, D. M. Eckert, V. M. Supekar, C. Bruckmann, A. Carfi, and A. Pessi. 2004. Structural characterization of the fusion-active complex of severe acute respiratory syndrome (SARS) coronavirus. Proc. Natl. Acad. Sci. USA101:8709-8714.
    OpenUrlAbstract/FREE Full Text
  160. 160.↵
    Ip, W. K., K. H. Chan, H. K. Law, G. H. Tso, E. K. Kong, W. H. Wong, Y. F. To, R. W. Yung, E. Y. Chow, K. L. Au, E. Y. Chan, W. Lim, J. C. Jensenius, M. W. Turner, J. S. Peiris, and Y. L. Lau. 2005. Mannose-binding lectin in severe acute respiratory syndrome coronavirus infection. J. Infect. Dis.191:1697-1704.
    OpenUrlCrossRefPubMedWeb of Science
  161. 161.↵
    Ito, N., E. C. Mossel, K. Narayanan, V. L. Popov, C. Huang, T. Inoue, C. J. Peters, and S. Makino. 2005. Severe acute respiratory syndrome coronavirus 3a protein is a viral structural protein. J. Virol.79:3182-3186.
    OpenUrlAbstract/FREE Full Text
  162. 162.↵
    Jeffers, S. A., S. M. Tusell, L. Gillim-Ross, E. M. Hemmila, J. E. Achenbach, G. J. Babcock, W. D. Thomas, Jr., L. B. Thackray, M. D. Young, R. J. Mason, D. M. Ambrosino, D. E. Wentworth, J. C. Demartini, and K. V. Holmes. 2004. CD209L (L-SIGN) is a receptor for severe acute respiratory syndrome coronavirus. Proc. Natl. Acad. Sci. USA101:15748-15753.
    OpenUrlAbstract/FREE Full Text
  163. 163.↵
    Jiang, Y., J. Xu, C. Zhou, Z. Wu, S. Zhong, J. Liu, W. Luo, T. Chen, Q. Qin, and P. Deng. 2005. Characterization of cytokine/chemokine profiles of severe acute respiratory syndrome. Am. J. Respir. Crit. Care Med.171:850-857.
    OpenUrlCrossRefPubMedWeb of Science
  164. 164.
    Jin, H., C. Xiao, Z. Chen, Y. Kang, Y. Ma, K. Zhu, Q. Xie, Y. Tu, Y. Yu, and B. Wang. 2005. Induction of Th1 type response by DNA vaccinations with N, M, and E genes against SARS-CoV in mice. Biochem. Biophys. Res. Commun.328:979-986.
    OpenUrlCrossRefPubMed
  165. 165.↵
    Jones, B. M., E. S. Ma, J. S. Peiris, P. C. Wong, J. C. Ho, B. Lam, K. N. Lai, and K. W. Tsang. 2004. Prolonged disturbances of in vitro cytokine production in patients with severe acute respiratory syndrome (SARS) treated with ribavirin and steroids. Clin. Exp. Immunol.135:467-473.
    OpenUrlCrossRefPubMedWeb of Science
  166. 166.↵
    Joseph, J. S., K. S. Saikatendu, V. Subramanian, B. W. Neuman, A. Brooun, M. Griffith, K. Moy, M. K. Yadav, J. Velasquez, M. J. Buchmeier, R. C. Stevens, and P. Kuhn. 2006. Crystal structure of nonstructural protein 10 from the severe acute respiratory syndrome coronavirus reveals a novel fold with two zinc-binding motifs. J. Virol.80:7894-7901.
    OpenUrlAbstract/FREE Full Text
  167. 167.
    Kamitani, W., K. Narayanan, C. Huang, K. Lokugamage, T. Ikegami, N. Ito, H. Kubo, and S. Makino. 2006. Severe acute respiratory syndrome coronavirus nsp1 protein suppresses host gene expression by promoting host mRNA degradation. Proc. Natl. Acad. Sci. USA103:12885-12890.
    OpenUrlAbstract/FREE Full Text
  168. 168.↵
    Kan, B., M. Wang, H. Jing, H. Xu, X. Jiang, M. Yan, W. Liang, H. Zheng, K. Wan, Q. Liu, B. Cui, Y. Xu, E. Zhang, H. Wang, J. Ye, G. Li, M. Li, Z. Cui, X. Qi, K. Chen, L. Du, K. Gao, Y. T. Zhao, X. Z. Zou, Y. J. Feng, Y. F. Gao, R. Hai, D. Yu, Y. Guan, and J. Xu. 2005. Molecular evolution analysis and geographic investigation of severe acute respiratory syndrome coronavirus-like virus in palm civets at an animal market and on farms. J. Virol.79:11892-11900.
    OpenUrlAbstract/FREE Full Text
  169. 169.↵
    Kanzawa, N., K. Nishigaki, T. Hayashi, Y. Ishii, S. Furukawa, A. Niiro, F. Yasui, M. Kohara, K. Morita, K. Matsushima, M. Q. Le, T. Masuda, and M. Kannagi. 2006. Augmentation of chemokine production by severe acute respiratory syndrome coronavirus 3a/X1 and 7a/X4 proteins through NF-kappaB activation. FEBS Lett.580:6807-6812.
    OpenUrlCrossRefPubMed
  170. 170.↵
    Kao, R. Y., W. H. Tsui, T. S. Lee, J. A. Tanner, R. M. Watt, J. D. Huang, L. Hu, G. Chen, Z. Chen, L. Zhang, T. He, K. H. Chan, H. Tse, A. P. To, L. W. Ng, B. C. Wong, H. W. Tsoi, D. Yang, D. D. Ho, and K. Y. Yuen. 2004. Identification of novel small-molecule inhibitors of severe acute respiratory syndrome-associated coronavirus by chemical genetics. Chem. Biol.11:1293-1299.
    OpenUrlCrossRefPubMed
  171. 171.↵
    Kapadia, S. U., J. K. Rose, E. Lamirande, L. Vogel, K. Subbarao, and A. Roberts. 2005. Long-term protection from SARS coronavirus infection conferred by a single immunization with an attenuated VSV-based vaccine. Virology340:174-182.
    OpenUrlCrossRefPubMedWeb of Science
  172. 172.
    Keng, C. T., Y. W. Choi, M. R. Welkers, D. Z. Chan, S. Shen, S. G. Lim, W. Hong, and Y. J. Tan. 2006. The human severe acute respiratory syndrome coronavirus (SARS-CoV) 8b protein is distinct from its counterpart in animal SARS-CoV and down-regulates the expression of the envelope protein in infected cells. Virology354:132-142.
    OpenUrlCrossRefPubMed
  173. 173.
    Keyaerts, E., L. Vijgen, L. Chen, P. Maes, G. Hedenstierna, and M. Van Ranst. 2004. Inhibition of SARS-coronavirus infection in vitro by S-nitroso-N-acetylpenicillamine, a nitric oxide donor compound. Int. J. Infect. Dis.8:223-226.
    OpenUrlCrossRefPubMedWeb of Science
  174. 174.↵
    Keyaerts, E., L. Vijgen, P. Maes, J. Neyts, and M. Van Ranst. 2004. In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine. Biochem. Biophys. Res. Commun.323:264-268.
    OpenUrlCrossRefPubMedWeb of Science
  175. 175.
    Khan, S., B. C. Fielding, T. H. Tan, C. F. Chou, S. Shen, S. G. Lim, W. Hong, and Y. J. Tan. 2006. Over-expression of severe acute respiratory syndrome coronavirus 3b protein induces both apoptosis and necrosis in Vero E6 cells. Virus Res.122:20-27.
    OpenUrlCrossRefPubMed
  176. 176.↵
    Kim, T. W., J. H. Lee, C. F. Hung, S. Peng, R. Roden, M. C. Wang, R. Viscidi, Y. C. Tsai, L. He, P. J. Chen, D. A. Boyd, and T. C. Wu. 2004. Generation and characterization of DNA vaccines targeting the nucleocapsid protein of severe acute respiratory syndrome coronavirus. J. Virol.78:4638-4645.
    OpenUrlAbstract/FREE Full Text
  177. 177.↵
    Kliger, Y., and E. Y. Levanon. 2003. Cloaked similarity between HIV-1 and SARS-CoV suggests an anti-SARS strategy. BMC Microbiol.3:20.
    OpenUrlCrossRefPubMed
  178. 178.↵
    Kopecky-Bromberg, S. A., L. Martinez-Sobrido, M. Frieman, R. A. Baric, and P. Palese. 2007. Severe acute respiratory syndrome coronavirus open reading frame (ORF) 3b, ORF 6, and nucleocapsid proteins function as interferon antagonists. J. Virol.81:548-557.
    OpenUrlAbstract/FREE Full Text
  179. 179.
    Kopecky-Bromberg, S. A., L. Martinez-Sobrido, and P. Palese. 2006. 7a protein of severe acute respiratory syndrome coronavirus inhibits cellular protein synthesis and activates p38 mitogen-activated protein kinase. J. Virol.80:785-793.
    OpenUrlAbstract/FREE Full Text
  180. 180.↵
    Ksiazek, T. G., D. Erdman, C. S. Goldsmith, S. R. Zaki, T. Peret, S. Emery, S. Tong, C. Urbani, J. A. Comer, W. Lim, P. E. Rollin, S. F. Dowell, A. E. Ling, C. D. Humphrey, W. J. Shieh, J. Guarner, C. D. Paddock, P. Rota, B. Fields, J. DeRisi, J. Y. Yang, N. Cox, J. M. Hughes, J. W. LeDuc, W. J. Bellini, and L. J. Anderson. 2003. A novel coronavirus associated with severe acute respiratory syndrome. N. Engl. J. Med.348:1953-1966.
    OpenUrlCrossRefPubMedWeb of Science
  181. 181.↵
    Kuba, K., Y. Imai, S. Rao, H. Gao, F. Guo, B. Guan, Y. Huan, P. Yang, Y. Zhang, W. Deng, L. Bao, B. Zhang, G. Liu, Z. Wang, M. Chappell, Y. Liu, D. Zheng, A. Leibbrandt, T. Wada, A. S. Slutsky, D. Liu, C. Qin, C. Jiang, and J. M. Penninger. 2005. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat. Med.11:875-879.
    OpenUrlCrossRefPubMedWeb of Science
  182. 182.↵
    Kuiken, T., R. A. Fouchier, M. Schutten, G. F. Rimmelzwaan, G. van Amerongen, D. van Riel, J. D. Laman, T. de Jong, G. van Doornum, W. Lim, A. E. Ling, P. K. Chan, J. S. Tam, M. C. Zambon, R. Gopal, C. Drosten, S. van der Werf, N. Escriou, J. C. Manuguerra, K. Stohr, J. S. Peiris, and A. D. Osterhaus. 2003. Newly discovered coronavirus as the primary cause of severe acute respiratory syndrome. Lancet362:263-270.
    OpenUrlCrossRefPubMedWeb of Science
  183. 183.↵
    Kwan, M. Y., W. M. Chan, P. W. Ko, C. W. Leung, and M. C. Chiu. 2004. Severe acute respiratory syndrome can be mild in children. Pediatr. Infect. Dis. J.23:1172-1174.
    OpenUrlPubMed
  184. 184.↵
    Lai, E. K., H. Deif, E. A. LaMere, D. H. Pham, B. Wolff, S. Ward, B. Mederski, and M. R. Loutfy. 2005. Severe acute respiratory syndrome: quantitative assessment from chest radiographs with clinical and prognostic correlation. Am. J. Roentgenol.184:255-263.
    OpenUrlPubMedWeb of Science
  185. 185.↵
    Lai, M. Y., P. K. Cheng, and W. W. Lim. 2005. Survival of severe acute respiratory syndrome coronavirus. Clin. Infect. Dis.41:e67-e71.
    OpenUrlCrossRefPubMedWeb of Science
  186. 186.
    Lau, A. C., L. K. So, F. P. Miu, R. W. Yung, E. Poon, T. M. Cheung, and L. Y. Yam. 2004. Outcome of coronavirus-associated severe acute respiratory syndrome using a standard treatment protocol. Respirology9:173-183.
    OpenUrlCrossRefPubMed
  187. 187.↵
    Lau, J. T., X. Yang, P. C. Leung, L. Chan, E. Wong, C. Fong, and H. Y. Tsui. 2004. SARS in three categories of hospital workers, Hong Kong. Emerg. Infect. Dis.10:1399-1404.
    OpenUrlPubMedWeb of Science
  188. 188.↵
    Lau, K. K., W. C. Yu, C. M. Chu, S. T. Lau, B. Sheng, and K. Y. Yuen. 2004. Possible central nervous system infection by SARS coronavirus. Emerg. Infect. Dis.10:342-344.
    OpenUrlCrossRefPubMedWeb of Science
  189. 189.↵
    Lau, S. K., X. Y. Che, P. C. Woo, B. H. Wong, V. C. Cheng, G. K. Woo, I. F. Hung, R. W. Poon, K. H. Chan, J. S. Peiris, and K. Y. Yuen. 2005. SARS coronavirus detection methods. Emerg. Infect. Dis.11:1108-1111.
    OpenUrlCrossRefPubMedWeb of Science
  190. 190.↵
    Lau, S. K., P. C. Woo, K. S. Li, Y. Huang, H. W. Tsoi, B. H. Wong, S. S. Wong, S. Y. Leung, K. H. Chan, and K. Y. Yuen. 2005. Severe acute respiratory syndrome coronavirus-like virus in Chinese horseshoe bats. Proc. Natl. Acad. Sci. USA102:14040-14045.
    OpenUrlAbstract/FREE Full Text
  191. 191.↵
    Lau, S. K., P. C. Woo, B. H. Wong, H. W. Tsoi, G. K. Woo, R. W. Poon, K. H. Chan, W. I. Wei, J. S. Peiris, and K. Y. Yuen. 2004. Detection of severe acute respiratory syndrome (SARS) coronavirus nucleocapsid protein in SARS patients by enzyme-linked immunosorbent assay. J. Clin. Microbiol.42:2884-2889.
    OpenUrlAbstract/FREE Full Text
  192. 192.↵
    Law, A. H., D. C. Lee, B. K. Cheung, H. C. Yim, and A. S. Lau. 2007. Role for nonstructural protein 1 of severe acute respiratory syndrome coronavirus in chemokine dysregulation. J. Virol.81:416-422.
    OpenUrlAbstract/FREE Full Text
  193. 193.
    Law, P. T., C. H. Wong, T. C. Au, C. P. Chuck, S. K. Kong, P. K. Chan, K. F. To, A. W. Lo, J. Y. Chan, Y. K. Suen, H. Y. Chan, K. P. Fung, M. M. Waye, J. J. Sung, Y. M. Lo, and S. K. Tsui. 2005. The 3a protein of severe acute respiratory syndrome-associated coronavirus induces apoptosis in Vero E6 cells. J. Gen. Virol.86:1921-1930.
    OpenUrlCrossRefPubMedWeb of Science
  194. 194.
    Lawler, J. V., T. P. Endy, L. E. Hensley, A. Garrison, E. A. Fritz, M. Lesar, R. S. Baric, D. A. Kulesh, D. A. Norwood, L. P. Wasieloski, M. P. Ulrich, T. R. Slezak, E. Vitalis, J. W. Huggins, P. B. Jahrling, and J. Paragas. 2006. Cynomolgus macaque as an animal model for severe acute respiratory syndrome. PLoS Med.3:e149.
    OpenUrlCrossRefPubMed
  195. 195.↵
    Lee, D. T., Y. K. Wing, H. C. Leung, J. J. Sung, Y. K. Ng, G. C. Yiu, R. Y. Chen, and H. F. Chiu. 2004. Factors associated with psychosis among patients with severe acute respiratory syndrome: a case-control study. Clin. Infect. Dis.39:1247-1249.
    OpenUrlCrossRefPubMed
  196. 196.↵
    Lee, N., K. C. A. Chan, D. S. Hui, E. K. Ng, A. Wu, R. W. Chiu, V. W. Wong, P. K. Chan, K. T. Wong, E. Wong, C. S. Cockram, J. S. Tam, J. J. Sung, and Y. M. Lo. 2004. Effects of early corticosteroid treatment on plasma SARS-associated coronavirus RNA concentrations in adult patients. J. Clin. Virol.31:304-309.
    OpenUrlCrossRefPubMedWeb of Science
  197. 197.↵
    Lee, N., D. Hui, A. Wu, P. Chan, P. Cameron, G. M. Joynt, A. Ahuja, M. Y. Yung, C. B. Leung, K. F. To, S. F. Lui, C. C. Szeto, S. Chung, and J. J. Sung. 2003. A major outbreak of severe acute respiratory syndrome in Hong Kong. N. Engl. J. Med.348:1986-1994.
    OpenUrlCrossRefPubMedWeb of Science
  198. 198.↵
    Lee, P. P., W. H. Wong, G. M. Leung, S. S. Chiu, K. H. Chan, J. S. Peiris, T. H. Lam, and Y. L. Lau. 2006. Risk-stratified seroprevalence of severe acute respiratory syndrome coronavirus among children in Hong Kong. Pediatrics117:e1156-e1162.
    OpenUrlAbstract/FREE Full Text
  199. 199.
    Leong, H. N., B. Ang, A. Earnest, C. Teoh, W. Xu, and Y. S. Leo. 2004. Investigational use of ribavirin in the treatment of severe acute respiratory syndrome, Singapore, 2003. Trop. Med. Int. Health9:923-927.
    OpenUrlCrossRefPubMedWeb of Science
  200. 200.↵
    Leow, M. K., D. S. Kwek, A. W. Ng, K. C. Ong, G. J. Kaw, and L. S. Lee. 2005. Hypocortisolism in survivors of severe acute respiratory syndrome (SARS). Clin. Endocrinol. (Oxford)63:197-202.
    OpenUrlCrossRefPubMed
  201. 201.↵
    Leung, G. M., P. H. Chung, T. Tsang, W. Lim, S. K. Chan, P. Chau, C. A. Donnelly, A. C. Ghani, C. Fraser, S. Riley, N. M. Ferguson, R. M. Anderson, Y. L. Law, T. Mok, T. Ng, A. Fu, P. Y. Leung, J. S. Peiris, T. H. Lam, and A. J. Hedley. 2004. SARS-CoV antibody prevalence in all Hong Kong patient contacts. Emerg. Infect. Dis.10:1653-1656.
    OpenUrlCrossRefPubMedWeb of Science
  202. 202.↵
    Leung, G. M., A. J. Hedley, L. M. Ho, P. Chau, I. O. Wong, T. Q. Thach, A. C. Ghani, C. A. Donnelly, C. Fraser, S. Riley, N. M. Ferguson, R. M. Anderson, T. Tsang, P. Y. Leung, V. Wong, J. C. Chan, E. Tsui, S. V. Lo, and T. H. Lam. 2004. The epidemiology of severe acute respiratory syndrome in the 2003 Hong Kong epidemic: an analysis of all 1755 patients. Ann. Intern. Med.141:662-673.
    OpenUrlCrossRefPubMedWeb of Science
  203. 203.↵
    Leung, G. M., W. W. Lim, L. M. Ho, T. H. Lam, A. C. Ghani, C. A. Donnelly, C. Fraser, S. Riley, N. M. Ferguson, R. M. Anderson, and A. J. Hedley. 2006. Seroprevalence of IgG antibodies to SARS-coronavirus in asymptomatic or subclinical population groups. Epidemiol. Infect.134:211-221.
    OpenUrlPubMedWeb of Science
  204. 204.
    Leung, T. W., K. S. Wong, A. C. Hui, K. F. To, S. T. Lai, W. F. Ng, and H. K. Ng. 2005. Myopathic changes associated with severe acute respiratory syndrome: a postmortem case series. Arch. Neurol.62:1113-1117.
    OpenUrlCrossRefPubMed
  205. 205.↵
    Leung, W. K., K. F. To, P. K. Chan, H. L. Chan, A. K. Wu, N. Lee, K. Y. Yuen, and J. J. Sung. 2003. Enteric involvement of severe acute respiratory syndrome-associated coronavirus infection. Gastroenterology125:1011-1017.
    OpenUrlCrossRefPubMedWeb of Science
  206. 206.↵
    Li, F., W. Li, M. Farzan, and S. C. Harrison. 2005. Structure of SARS coronavirus spike receptor-binding domain complexed with receptor. Science309:1864-1868.
    OpenUrlAbstract/FREE Full Text
  207. 207.↵
    Li, G., X. Chen, and A. Xu. 2003. Profile of specific antibodies to the SARS-associated coronavirus. N. Engl. J. Med.349:508-509.
    OpenUrlCrossRefPubMedWeb of Science
  208. 208.↵
    Li, L., J. Wo, J. Shao, H. Zhu, N. Wu, M. Li, H. Yao, M. Hu, and R. H. Dennin. 2003. SARS-coronavirus replicates in mononuclear cells of peripheral blood (PBMCs) from SARS patients. J. Clin. Virol.28:239-244.
    OpenUrlCrossRefPubMedWeb of Science
  209. 209.↵
    Li, L. H., Y. L. Shi, P. Li, D. X. Xu, G. P. Wan, X. Q. Gu, X. L. Zhang, Q. J. Ma, and C. Cao. 2003. Detection and analysis of SARS coronavirus-specific antibodies in sera from non-SARS children. Di Yi Jun Yi Da Xue Xue Bao23:1085-1087. (In Chinese.)
    OpenUrlPubMed
  210. 210.
    Li, Q., L. Wang, C. Dong, Y. Che, L. Jiang, L. Liu, H. Zhao, Y. Liao, Y. Sheng, S. Dong, and S. Ma. 2005. The interaction of the SARS coronavirus non-structural protein 10 with the cellular oxido-reductase system causes an extensive cytopathic effect. J. Clin. Virol.34:133-139.
    OpenUrlCrossRefPubMedWeb of Science
  211. 211.↵
    Li, S. S., C. W. Cheng, C. L. Fu, Y. H. Chan, M. P. Lee, J. W. Chan, and S. F. Yiu. 2003. Left ventricular performance in patients with severe acute respiratory syndrome: a 30-day echocardiographic follow-up study. Circulation108:1798-1803.
    OpenUrlAbstract/FREE Full Text
  212. 212.
    Li, S. Y., C. Chen, H. Q. Zhang, H. Y. Guo, H. Wang, L. Wang, X. Zhang, S. N. Hua, J. Yu, P. G. Xiao, R. S. Li, and X. Tan. 2005. Identification of natural compounds with antiviral activities against SARS-associated coronavirus. Antivir. Res.67:18-23.
    OpenUrlCrossRefPubMedWeb of Science
  213. 213.↵
    Li, T., Z. Qiu, L. Zhang, Y. Han, W. He, Z. Liu, X. Ma, H. Fan, W. Lu, J. Xie, H. Wang, G. Deng, and A. Wang. 2004. Significant changes of peripheral T lymphocyte subsets in patients with severe acute respiratory syndrome. J. Infect. Dis.189:648-651.
    OpenUrlCrossRefPubMedWeb of Science
  214. 214.
    Li, W., M. J. Moore, N. Vasilieva, J. Sui, S. K. Wong, M. A. Berne, M. Somasundaran, J. L. Sullivan, K. Luzuriaga, T. C. Greenough, H. Choe, and M. Farzan. 2003. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature426:450-454.
    OpenUrlCrossRefPubMed
  215. 215.↵
    Li, W., Z. Shi, M. Yu, W. Ren, C. Smith, J. H. Epstein, H. Wang, G. Crameri, Z. Hu, H. Zhang, J. Zhang, J. McEachern, H. Field, P. Daszak, B. T. Eaton, S. Zhang, and L. F. Wang. 2005. Bats are natural reservoirs of SARS-like coronaviruses. Science310:676-679.
    OpenUrlAbstract/FREE Full Text
  216. 216.↵
    Li, W., C. Zhang, J. Sui, J. H. Kuhn, M. J. Moore, S. Luo, S. K. Wong, I. C. Huang, K. Xu, N. Vasilieva, A. Murakami, Y. He, W. A. Marasco, Y. Guan, H. Choe, and M. Farzan. 2005. Receptor and viral determinants of SARS-coronavirus adaptation to human ACE2. EMBO J.24:1634-1643.
    OpenUrlAbstract/FREE Full Text
  217. 217.
    Li, Y. Q., Z. L. Li, W. J. Zhao, R. X. Wen, Q. W. Meng, and Y. Zeng. 2006. Synthesis of stilbene derivatives with inhibition of SARS coronavirus replication. Eur. J. Med. Chem.41:1084-1089.
    OpenUrlCrossRefPubMed
  218. 218.
    Liang, G., Q. Chen, J. Xu, Y. Liu, W. Lim, J. S. Peiris, L. J. Anderson, L. Ruan, H. Li, B. Kan, B. Di, P. Cheng, K. H. Chan, D. D. Erdman, S. Gu, X. Yan, W. Liang, D. Zhou, L. Haynes, S. Duan, X. Zhang, H. Zheng, Y. Gao, S. Tong, D. Li, L. Fang, P. Qin, and W. Xu. 2004. Laboratory diagnosis of four recent sporadic cases of community-acquired SARS, Guangdong Province, China. Emerg. Infect. Dis.10:1774-1781.
    OpenUrlCrossRefPubMedWeb of Science
  219. 219.
    Liang, L., C. He, M. Lei, S. Li, Y. Hao, H. Zhu, and Q. Duan. 2005. Pathology of guinea pigs experimentally infected with a novel reovirus and coronavirus isolated from SARS patients. DNA Cell Biol.24:485-490.
    OpenUrlCrossRefPubMed
  220. 220.
    Liao, Q. J., L. B. Ye, K. A. Timani, Y. C. Zeng, Y. L. She, L. Ye, and Z. H. Wu. 2005. Activation of NF-kappaB by the full-length nucleocapsid protein of the SARS coronavirus. Acta Biochim. Biophys. Sin. (Shanghai)37:607-612.
    OpenUrlCrossRefPubMed
  221. 221.↵
    Lim, P. L., A. Kurup, G. Gopalakrishna, K. P. Chan, C. W. Wong, L. C. Ng, S. Y. Se-Thoe, L. Oon, X. Bai, L. W. Stanton, Y. Ruan, L. D. Miller, V. B. Vega, L. James, P. L. Ooi, C. S. Kai, S. J. Olsen, B. Ang, and Y. S. Leo. 2004. Laboratory-acquired severe acute respiratory syndrome. N. Engl. J. Med.350:1740-1745.
    OpenUrlCrossRefPubMedWeb of Science
  222. 222.
    Lin, C. W., K. H. Lin, T. H. Hsieh, S. Y. Shiu, and J. Y. Li. 2006. Severe acute respiratory syndrome coronavirus 3C-like protease-induced apoptosis. FEMS Immunol. Med. Microbiol.46:375-380.
    OpenUrlCrossRefPubMed
  223. 223.↵
    Lin, M., H. K. Tseng, J. A. Trejaut, H. L. Lee, J. H. Loo, C. C. Chu, P. J. Chen, Y. W. Su, K. H. Lim, Z. U. Tsai, R. Y. Lin, R. S. Lin, and C. H. Huang. 2003. Association of HLA class I with severe acute respiratory syndrome coronavirus infection. BMC Med. Genet.4:9.
    OpenUrlCrossRefPubMed
  224. 224.↵
    Lindner, H. A., N. Fotouhi-Ardakani, V. Lytvyn, P. Lachance, T. Sulea, and R. Menard. 2005. The papain-like protease from the severe acute respiratory syndrome coronavirus is a deubiquitinating enzyme. J. Virol.79:15199-15208.
    OpenUrlAbstract/FREE Full Text
  225. 225.↵
    Lipsitch, M., T. Cohen, B. Cooper, J. M. Robins, S. Ma, L. James, G. Gopalakrishna, S. K. Chew, C. C. Tan, M. H. Samore, D. Fisman, and M. Murray. 2003. Transmission dynamics and control of severe acute respiratory syndrome. Science300:1966-1970.
    OpenUrlAbstract/FREE Full Text
  226. 226.
    Liu, I. J., P. J. Chen, S. H. Yeh, Y. P. Chiang, L. M. Huang, M. F. Chang, S. Y. Chen, P. C. Yang, S. C. Chang, and W. K. Wang. 2005. Immunofluorescence assay for detection of the nucleocapsid antigen of the severe acute respiratory syndrome (SARS)-associated coronavirus in cells derived from throat wash samples of patients with SARS. J. Clin. Microbiol.43:2444-2448.
    OpenUrlAbstract/FREE Full Text
  227. 227.↵
    Liu, S., G. Xiao, Y. Chen, Y. He, J. Niu, C. R. Escalante, H. Xiong, J. Farmar, A. K. Debnath, P. Tien, and S. Jiang. 2004. Interaction between heptad repeat 1 and 2 regions in spike protein of SARS-associated coronavirus: implications for virus fusogenic mechanism and identification of fusion inhibitors. Lancet363:938-947.
    OpenUrlCrossRefPubMedWeb of Science
  228. 228.↵
    Liu, Y. N., B. X. Fan, X. Q. Fang, B. X. Yu, and L. A. Chen. 2003. The quantitative detection of anti-coronavirus antibody titer in medical personnel closely contacted with severe acute respiratory syndrome patients. Zhonghua Jie He He Hu Xi Za Zhi26:583-585. (In Chinese.)
    OpenUrlPubMed
  229. 229.↵
    Loon, S. C., S. C. Teoh, L. L. Oon, S. Y. Se-Thoe, A. E. Ling, Y. S. Leo, and H. N. Leong. 2004. The severe acute respiratory syndrome coronavirus in tears. Br. J. Ophthalmol.88:861-863.
    OpenUrlAbstract/FREE Full Text
  230. 230.
    Louie, L., A. E. Simor, S. Chong, K. Luinstra, A. Petrich, J. Mahony, M. Smieja, G. Johnson, F. Gharabaghi, R. Tellier, B. M. Willey, S. Poutanen, T. Mazzulli, G. Broukhanski, F. Jamieson, M. Louie, and S. Richardson. 2006. Detection of severe acute respiratory syndrome coronavirus in stool specimens by commercially available real-time reverse transcriptase PCR assays. J. Clin. Microbiol.44:4193-4196.
    OpenUrlAbstract/FREE Full Text
  231. 231.↵
    Loutfy, M. R., L. M. Blatt, K. A. Siminovitch, S. Ward, B. Wolff, H. Lho, D. H. Pham, H. Deif, E. A. LaMere, M. Chang, K. C. Kain, G. A. Farcas, P. Ferguson, M. Latchford, G. Levy, J. W. Dennis, E. K. Lai, and E. N. Fish. 2003. Interferon alfacon-1 plus corticosteroids in severe acute respiratory syndrome: a preliminary study. JAMA290:3222-3228.
    OpenUrlCrossRefPubMedWeb of Science
  232. 232.↵
    Lu, A., H. Zhang, X. Zhang, H. Wang, Q. Hu, L. Shen, B. S. Schaffhausen, W. Hou, and L. Li. 2004. Attenuation of SARS coronavirus by a short hairpin RNA expression plasmid targeting RNA-dependent RNA polymerase. Virology324:84-89.
    OpenUrlCrossRefPubMed
  233. 233.↵
    Lu, J. H., Z. M. Guo, W. Y. Han, G. L. Wang, D. M. Zhang, Y. F. Wang, S. Y. Sun, Q. H. Yang, H. Y. Zheng, B. L. Wong, and N. S. Zhong. 2005. Preparation and development of equine hyperimmune globulin F(ab′)2 against severe acute respiratory syndrome coronavirus. Acta Pharmacol. Sin.26:1479-1484.
    OpenUrlCrossRefPubMed
  234. 234.↵
    Lu, W., B. J. Zheng, K. Xu, W. Schwarz, L. Du, C. K. Wong, J. Chen, S. Duan, V. Deubel, and B. Sun. 2006. Severe acute respiratory syndrome-associated coronavirus 3a protein forms an ion channel and modulates virus release. Proc. Natl. Acad. Sci. USA103:12540-12545.
    OpenUrlAbstract/FREE Full Text
  235. 235.↵
    Manopo, I., L. Lu, Q. He, L. L. Chee, S. W. Chan, and J. Kwang. 2005. Evaluation of a safe and sensitive spike protein-based immunofluorescence assay for the detection of antibody responses to SARS-CoV. J. Immunol. Methods296:37-44.
    OpenUrlCrossRefPubMed
  236. 236.↵
    Marra, M. A., S. J. Jones, C. R. Astell, R. A. Holt, A. Brooks-Wilson, Y. S. Butterfield, J. Khattra, J. K. Asano, S. A. Barber, S. Y. Chan, A. Cloutier, S. M. Coughlin, D. Freeman, N. Girn, O. L. Griffith, S. R. Leach, M. Mayo, H. McDonald, S. B. Montgomery, P. K. Pandoh, A. S. Petrescu, A. G. Robertson, J. E. Schein, A. Siddiqui, D. E. Smailus, J. M. Stott, G. S. Yang, F. Plummer, A. Andonov, H. Artsob, N. Bastien, K. Bernard, T. F. Booth, D. Bowness, M. Czub, M. Drebot, L. Fernando, R. Flick, M. Garbutt, M. Gray, A. Grolla, S. Jones, H. Feldmann, A. Meyers, A. Kabani, Y. Li, S. Normand, U. Stroher, G. A. Tipples, S. Tyler, R. Vogrig, D. Ward, B. Watson, R. C. Brunham, M. Krajden, M. Petric, D. M. Skowronski, C. Upton, and R. L. Roper. 2003. The genome sequence of the SARS-associated coronavirus. Science300:1399-1404.
    OpenUrlAbstract/FREE Full Text
  237. 237.↵
    Martina, B. E., B. L. Haagmans, T. Kuiken, R. A. Fouchier, G. F. Rimmelzwaan, G. Van Amerongen, J. S. Peiris, W. Lim, and A. D. Osterhaus. 2003. Virology: SARS virus infection of cats and ferrets. Nature425:915.
    OpenUrlCrossRefPubMed
  238. 238.↵
    Maunder, R. G., W. J. Lancee, K. E. Balderson, J. P. Bennett, B. Borgundvaag, S. Evans, C. M. Fernandes, D. S. Goldbloom, M. Gupta, J. J. Hunter, L. M. Hall, L. M. Nagle, C. Pain, S. S. Peczeniuk, G. Raymond, N. Read, S. B. Rourke, R. J. Steinberg, T. E. Stewart, S. VanDeVelde-Coke, G. G. Veldhorst, and D. A. Wasylenki. 2006. Long-term psychological and occupational effects of providing hospital healthcare during SARS outbreak. Emerg. Infect. Dis.12:1924-1932.
    OpenUrlCrossRefPubMed
  239. 239.↵
    McAuliffe, J., L. Vogel, A. Roberts, G. Fahle, S. Fischer, W. J. Shieh, E. Butler, S. Zaki, M. St. Claire, B. Murphy, and K. Subbarao. 2004. Replication of SARS coronavirus administered into the respiratory tract of African green, rhesus and cynomolgus monkeys. Virology330:8-15.
    OpenUrlCrossRefPubMedWeb of Science
  240. 240.↵
    McCray, P. B., Jr., L. Pewe, C. Wohlford-Lenane, M. Hickey, L. Manzel, L. Shi, J. Netland, H. P. Jia, C. Halabi, C. D. Sigmund, D. K. Meyerholz, P. Kirby, D. C. Look, and S. Perlman. 2007. Lethal infection of K18-hACE2 mice infected with severe acute respiratory syndrome coronavirus. J. Virol.81:813-821.
    OpenUrlAbstract/FREE Full Text
  241. 241.
    Meier, C., A. R. Aricescu, R. Assenberg, R. T. Aplin, R. J. Gilbert, J. M. Grimes, and D. I. Stuart. 2006. The crystal structure of ORF-9b, a lipid binding protein from the SARS coronavirus. Structure14:1157-1165.
    OpenUrlCrossRefPubMed
  242. 242.↵
    Minskaia, E., T. Hertzig, A. E. Gorbalenya, V. Campanacci, C. Cambillau, B. Canard, and J. Ziebuhr. 2006. Discovery of an RNA virus 3′→5′ exoribonuclease that is critically involved in coronavirus RNA synthesis. Proc. Natl. Acad. Sci. USA103:5108-5113.
    OpenUrlAbstract/FREE Full Text
  243. 243.↵
    Morgenstern, B., M. Michaelis, P. C. Baer, H. W. Doerr, and J. Cinatl, Jr. 2005. Ribavirin and interferon-beta synergistically inhibit SARS-associated coronavirus replication in animal and human cell lines. Biochem. Biophys. Res. Commun.326:905-908.
    OpenUrlCrossRefPubMedWeb of Science
  244. 244.↵
    Nagata, N., N. Iwata, H. Hasegawa, S. Fukushi, M. Yokoyama, A. Harashima, Y. Sato, M. Saijo, S. Morikawa, and T. Sata. 2007. Participation of both host and virus factors in induction of severe acute respiratory syndrome (SARS) in F344 rats infected with SARS coronavirus. J. Virol.81:1848-1857.
    OpenUrlAbstract/FREE Full Text
  245. 245.↵
    Nelson, C. A., A. Pekosz, C. A. Lee, M. S. Diamond, and D. H. Fremont. 2005. Structure and intracellular targeting of the SARS-coronavirus Orf7a accessory protein. Structure13:75-85.
    OpenUrlCrossRefPubMed
  246. 246.
    Neuman, B. W., D. A. Stein, A. D. Kroeker, M. J. Churchill, A. M. Kim, P. Kuhn, P. Dawson, H. M. Moulton, R. K. Bestwick, P. L. Iversen, and M. J. Buchmeier. 2005. Inhibition, escape, and attenuated growth of severe acute respiratory syndrome coronavirus treated with antisense morpholino oligomers. J. Virol.79:9665-9676.
    OpenUrlAbstract/FREE Full Text
  247. 247.↵
    Ng, C. K., J. W. Chan, T. L. Kwan, T. S. To, Y. H. Chan, F. Y. Ng, and T. Y. Mok. 2004. Six month radiological and physiological outcomes in severe acute respiratory syndrome (SARS) survivors. Thorax59:889-891.
    OpenUrlAbstract/FREE Full Text
  248. 248.↵
    Ng, K. H., A. K. Wu, V. C. Cheng, B. S. Tang, C. Y. Chan, C. Y. Yung, S. H. Luk, T. W. Lee, L. Chow, and K. Y. Yuen. 2005. Pulmonary artery thrombosis in a patient with severe acute respiratory syndrome. Postgrad. Med. J.81:e3.
    OpenUrlAbstract/FREE Full Text
  249. 249.↵
    Ng, M. H., K. M. Lau, L. Li, S. H. Cheng, W. Y. Chan, P. K. Hui, B. Zee, C. B. Leung, and J. J. Sung. 2004. Association of human-leukocyte-antigen class I (B*0703) and class II (DRB1*0301) genotypes with susceptibility and resistance to the development of severe acute respiratory syndrome. J. Infect. Dis.190:515-518.
    OpenUrlCrossRefPubMedWeb of Science
  250. 250.↵
    Nicholls, J. M., L. L. Poon, K. C. Lee, W. F. Ng, S. T. Lai, C. Y. Leung, C. M. Chu, P. K. Hui, K. L. Mak, W. Lim, K. W. Yan, K. H. Chan, N. C. Tsang, Y. Guan, K. Y. Yuen, and J. S. Peiris. 2003. Lung pathology of fatal severe acute respiratory syndrome. Lancet361:1773-1778.
    OpenUrlCrossRefPubMedWeb of Science
  251. 251.↵
    Normile, D. 2004. Infectious diseases. Mounting lab accidents raise SARS fears. Science304:659-661.
    OpenUrlAbstract/FREE Full Text
  252. 252.↵
    Normile, D. 2004. Infectious diseases. Second lab accident fuels fears about SARS. Science303:26.
    OpenUrlAbstract/FREE Full Text
  253. 253.↵
    Okabayashi, T., H. Kariwa, S. Yokota, S. Iki, T. Indoh, N. Yokosawa, I. Takashima, H. Tsutsumi, and N. Fujii. 2006. Cytokine regulation in SARS coronavirus infection compared to other respiratory virus infections. J. Med. Virol.78:417-424.
    OpenUrlCrossRefPubMed
  254. 254.↵
    Olsen, S. J., H. L. Chang, T. Y. Cheung, A. F. Tang, T. L. Fisk, S. P. Ooi, H. W. Kuo, D. D. Jiang, K. T. Chen, J. Lando, K. H. Hsu, T. J. Chen, and S. F. Dowell. 2003. Transmission of the severe acute respiratory syndrome on aircraft. N. Engl. J. Med.349:2416-2422.
    OpenUrlCrossRefPubMedWeb of Science
  255. 255.↵
    Ong, K. C., A. W. Ng, L. S. Lee, G. Kaw, S. K. Kwek, M. K. Leow, and A. Earnest. 2004. Pulmonary function and exercise capacity in survivors of severe acute respiratory syndrome. Eur. Respir. J.24:436-442.
    OpenUrlAbstract/FREE Full Text
  256. 256.↵
    Orellana, C. 2004. Laboratory-acquired SARS raises worries on biosafety. Lancet Infect. Dis.4:64.
    OpenUrlPubMed
  257. 257.
    Paragas, J., L. M. Blatt, C. Hartmann, J. W. Huggins, and T. P. Endy. 2005. Interferon alfacon1 is an inhibitor of SARS-corona virus in cell-based models. Antivir. Res.66:99-102.
    OpenUrlCrossRefPubMedWeb of Science
  258. 258.↵
    Peiris, J. S., C. M. Chu, V. C. Cheng, K. S. Chan, I. F. Hung, L. L. Poon, K. I. Law, B. S. Tang, T. Y. Hon, C. S. Chan, K. H. Chan, J. S. Ng, B. J. Zheng, W. L. Ng, R. W. Lai, Y. Guan, and K. Y. Yuen. 2003. Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study. Lancet361:1767-1772.
    OpenUrlCrossRefPubMedWeb of Science
  259. 259.↵
    Peiris, J. S., S. T. Lai, L. L. Poon, Y. Guan, L. Y. Yam, W. Lim, J. Nicholls, W. K. Yee, W. W. Yan, M. T. Cheung, V. C. Cheng, K. H. Chan, D. N. Tsang, R. W. Yung, T. K. Ng, and K. Y. Yuen. 2003. Coronavirus as a possible cause of severe acute respiratory syndrome. Lancet361:1319-1325.
    OpenUrlCrossRefPubMedWeb of Science
  260. 260.↵
    Peiris, J. S., K. Y. Yuen, A. D. Osterhaus, and K. Stohr. 2003. The severe acute respiratory syndrome. N. Engl. J. Med.349:2431-2441.
    OpenUrlCrossRefPubMedWeb of Science
  261. 261.
    Peti, W., M. A. Johnson, T. Herrmann, B. W. Neuman, M. J. Buchmeier, M. Nelson, J. Joseph, R. Page, R. C. Stevens, P. Kuhn, and K. Wuthrich. 2005. Structural genomics of the severe acute respiratory syndrome coronavirus: nuclear magnetic resonance structure of the protein nsP7. J. Virol.79:12905-12913.
    OpenUrlAbstract/FREE Full Text
  262. 262.↵
    Pogrebnyak, N., M. Golovkin, V. Andrianov, S. Spitsin, Y. Smirnov, R. Egolf, and H. Koprowski. 2005. Severe acute respiratory syndrome (SARS) S protein production in plants: development of recombinant vaccine. Proc. Natl. Acad. Sci. USA102:9062-9067.
    OpenUrlAbstract/FREE Full Text
  263. 263.
    Poon, L. L., K. H. Chan, O. K. Wong, T. K. Cheung, I. Ng, B. Zheng, W. H. Seto, K. Y. Yuen, Y. Guan, and J. S. Peiris. 2004. Detection of SARS coronavirus in patients with severe acute respiratory syndrome by conventional and real-time quantitative reverse transcription-PCR assays. Clin. Chem.50:67-72.
    OpenUrlAbstract/FREE Full Text
  264. 264.↵
    Poon, L. L., K. H. Chan, O. K. Wong, W. C. Yam, K. Y. Yuen, Y. Guan, Y. M. Lo, and J. S. Peiris. 2003. Early diagnosis of SARS coronavirus infection by real time RT-PCR. J. Clin. Virol.28:233-238.
    OpenUrlCrossRefPubMedWeb of Science
  265. 265.↵
    Poon, L. L., D. K. Chu, K. H. Chan, O. K. Wong, T. M. Ellis, Y. H. Leung, S. K. Lau, P. C. Woo, K. Y. Suen, K. Y. Yuen, Y. Guan, and J. S. Peiris. 2005. Identification of a novel coronavirus in bats. J. Virol.79:2001-2009.
    OpenUrlAbstract/FREE Full Text
  266. 266.↵
    Poon, L. L., B. W. Wong, K. H. Chan, C. S. Leung, K. Y. Yuen, Y. Guan, and J. S. Peiris. 2004. A one step quantitative RT-PCR for detection of SARS coronavirus with an internal control for PCR inhibitors. J. Clin. Virol.30:214-217.
    OpenUrlCrossRefPubMedWeb of Science
  267. 267.
    Poon, L. L., B. W. Wong, K. H. Chan, S. S. Ng, K. Y. Yuen, Y. Guan, and J. S. Peiris. 2005. Evaluation of real-time reverse transcriptase PCR and real-time loop-mediated amplification assays for severe acute respiratory syndrome coronavirus detection. J. Clin. Microbiol.43:3457-3459.
    OpenUrlAbstract/FREE Full Text
  268. 268.↵
    Poon, L. L., O. K. Wong, K. H. Chan, W. Luk, K. Y. Yuen, J. S. Peiris, and Y. Guan. 2003. Rapid diagnosis of a coronavirus associated with severe acute respiratory syndrome (SARS). Clin. Chem.49:953-955.
    OpenUrlFREE Full Text
  269. 269.
    Poon, P. M., C. K. Wong, K. P. Fung, C. Y. Fong, E. L. Wong, J. T. Lau, P. C. Leung, S. K. Tsui, D. C. Wan, M. M. Waye, S. W. Au, C. B. Lau, and C. W. Lam. 2006. Immunomodulatory effects of a traditional Chinese medicine with potential antiviral activity: a self-control study. Am. J. Chin. Med.34:13-21.
    OpenUrlCrossRefPubMed
  270. 270.↵
    Poutanen, S. M., D. E. Low, B. Henry, S. Finkelstein, D. Rose, K. Green, R. Tellier, R. Draker, D. Adachi, M. Ayers, A. K. Chan, D. M. Skowronski, I. Salit, A. E. Simor, A. S. Slutsky, P. W. Doyle, M. Krajden, M. Petric, R. C. Brunham, and A. J. McGeer. 2003. Identification of severe acute respiratory syndrome in Canada. N. Engl. J. Med.348:1995-2005.
    OpenUrlCrossRefPubMedWeb of Science
  271. 271.
    Putics, A., W. Filipowicz, J. Hall, A. E. Gorbalenya, and J. Ziebuhr. 2005. ADP-ribose-1‴-monophosphatase: a conserved coronavirus enzyme that is dispensable for viral replication in tissue culture. J. Virol.79:12721-12731.
    OpenUrlAbstract/FREE Full Text
  272. 272.
    Qin, C., J. Wang, Q. Wei, M. She, W. A. Marasco, H. Jiang, X. Tu, H. Zhu, L. Ren, H. Gao, L. Guo, L. Huang, R. Yang, Z. Cong, L. Guo, Y. Wang, Y. Liu, Y. Sun, S. Duan, J. Qu, L. Chen, W. Tong, L. Ruan, P. Liu, H. Zhang, J. Zhang, H. Zhang, D. Liu, Q. Liu, T. Hong, and W. He. 2005. An animal model of SARS produced by infection of Macaca mulatta with SARS coronavirus. J. Pathol.206:251-259.
    OpenUrlCrossRefPubMedWeb of Science
  273. 273.
    Qiu, M., J. Wang, H. Wang, Z. Chen, E. Dai, Z. Guo, X. Wang, X. Pang, B. Fan, J. Wen, J. Wang, and R. Yang. 2005. Use of the COOH portion of the nucleocapsid protein in an antigen-capturing enzyme-linked immunosorbent assay for specific and sensitive detection of severe acute respiratory syndrome coronavirus. Clin. Diagn. Lab. Immunol.12:474-476.
    OpenUrlCrossRefPubMed
  274. 274.
    Qu, D., B. Zheng, X. Yao, Y. Guan, Z. H. Yuan, N. S. Zhong, L. W. Lu, J. P. Xie, and Y. M. Wen. 2005. Intranasal immunization with inactivated SARS-CoV (SARS-associated coronavirus) induced local and serum antibodies in mice. Vaccine23:924-931.
    OpenUrlCrossRefPubMed
  275. 275.↵
    Qu, X. X., P. Hao, X. J. Song, S. M. Jiang, Y. X. Liu, P. G. Wang, X. Rao, H. D. Song, S. Y. Wang, Y. Zuo, A. H. Zheng, M. Luo, H. L. Wang, F. Deng, H. Z. Wang, Z. H. Hu, M. X. Ding, G. P. Zhao, and H. K. Deng. 2005. Identification of two critical amino acid residues of the severe acute respiratory syndrome coronavirus spike protein for its variation in zoonotic tropism transition via a double substitution strategy. J. Biol. Chem.280:29588-29595.
    OpenUrlAbstract/FREE Full Text
  276. 276.↵
    Rabenau, H. F., J. Cinatl, B. Morgenstern, G. Bauer, W. Preiser, and H. W. Doerr. 2005. Stability and inactivation of SARS coronavirus. Med. Microbiol. Immunol.194:1-6.
    OpenUrlCrossRefPubMed
  277. 277.
    Radun, D., M. Niedrig, A. Ammon, and K. Stark. 2003. SARS: retrospective cohort study among German guests of the hotel ‘M, ’ Hong Kong Eur. Surveill.8:228-230.
    OpenUrl
  278. 278.↵
    Rainer, T. H., P. A. Cameron, D. Smit, K. L. Ong, A. N. Hung, D. C. Nin, A. T. Ahuja, L. C. Si, and J. J. Sung. 2003. Evaluation of WHO criteria for identifying patients with severe acute respiratory syndrome out of hospital: prospective observational study. BMJ326:1354-1358.
    OpenUrlAbstract/FREE Full Text
  279. 279.↵
    Ratia, K., K. S. Saikatendu, B. D. Santarsiero, N. Barretto, S. C. Baker, R. C. Stevens, and A. D. Mesecar. 2006. Severe acute respiratory syndrome coronavirus papain-like protease: structure of a viral deubiquitinating enzyme. Proc. Natl. Acad. Sci. USA103:5717-5722.
    OpenUrlAbstract/FREE Full Text
  280. 280.↵
    Reghunathan, R., M. Jayapal, L. Y. Hsu, H. H. Chng, D. Tai, B. P. Leung, and A. J. Melendez. 2005. Expression profile of immune response genes in patients with severe acute respiratory syndrome. BMC Immunol.6:2.
    OpenUrlCrossRefPubMed
  281. 281.↵
    Reilley, B., M. Van Herp, D. Sermand, and N. Dentico. 2003. SARS and Carlo Urbani. N. Engl. J. Med.348:1951-1952.
    OpenUrlCrossRefPubMedWeb of Science
  282. 282.↵
    Ren, W., W. Li, M. Yu, P. Hao, Y. Zhang, P. Zhou, S. Zhang, G. Zhao, Y. Zhong, S. Wang, L. F. Wang, and Z. Shi. 2006. Full-length genome sequences of two SARS-like coronaviruses in horseshoe bats and genetic variation analysis. J. Gen. Virol.87:3355-3359.
    OpenUrlCrossRefPubMedWeb of Science
  283. 283.↵
    Rest, J. S., and D. P. Mindell. 2003. SARS associated coronavirus has a recombinant polymerase and coronaviruses have a history of host-shifting. Infect. Genet. Evol.3:219-225.
    OpenUrlCrossRefPubMed
  284. 284.↵
    Ricagno, S., M. P. Egloff, R. Ulferts, B. Coutard, D. Nurizzo, V. Campanacci, C. Cambillau, J. Ziebuhr, and B. Canard. 2006. Crystal structure and mechanistic determinants of SARS coronavirus nonstructural protein 15 define an endoribonuclease family. Proc. Natl. Acad. Sci. USA103:11892-11897.
    OpenUrlAbstract/FREE Full Text
  285. 285.↵
    Riley, S., C. Fraser, C. A. Donnelly, A. C. Ghani, L. J. Abu-Raddad, A. J. Hedley, G. M. Leung, L. M. Ho, T. H. Lam, T. Q. Thach, P. Chau, K. P. Chan, S. V. Lo, P. Y. Leung, T. Tsang, W. Ho, K. H. Lee, E. M. Lau, N. M. Ferguson, and R. M. Anderson. 2003. Transmission dynamics of the etiological agent of SARS in Hong Kong: impact of public health interventions. Science300:1961-1966.
    OpenUrlAbstract/FREE Full Text
  286. 286.↵
    Roberts, A., D. Deming, C. D. Paddock, A. Cheng, B. Yount, L. Vogel, B. D. Herman, T. Sheahan, M. Heise, G. L. Genrich, S. R. Zaki, R. Baric, and K. Subbarao. 2007. A mouse-adapted SARS-coronavirus causes disease and mortality in BALB/c mice. PLoS Pathog.3:e5.
    OpenUrlCrossRefPubMed
  287. 287.↵
    Roberts, A., C. Paddock, L. Vogel, E. Butler, S. Zaki, and K. Subbarao. 2005. Aged BALB/c mice as a model for increased severity of severe acute respiratory syndrome in elderly humans. J. Virol.79:5833-5838.
    OpenUrlAbstract/FREE Full Text
  288. 288.↵
    Roberts, A., L. Vogel, J. Guarner, N. Hayes, B. Murphy, S. Zaki, and K. Subbarao. 2005. Severe acute respiratory syndrome coronavirus infection of golden Syrian hamsters. J. Virol.79:503-511.
    OpenUrlAbstract/FREE Full Text
  289. 289.↵
    Rockx, B., T. Sheahan, E. Donaldson, J. Harkema, A. Sims, M. Heise, R. Pickles, M. Cameron, D. Kelvin, and R. Baric. 2007. Synthetic reconstruction of zoonotic and early human severe acute respiratory syndrome coronavirus isolates that produce fatal disease in aged mice. J. Virol.81:7410-7423.
    OpenUrlAbstract/FREE Full Text
  290. 290.↵
    Rota, P. A., M. S. Oberste, S. S. Monroe, W. A. Nix, R. Campagnoli, J. P. Icenogle, S. Penaranda, B. Bankamp, K. Maher, M. H. Chen, S. Tong, A. Tamin, L. Lowe, M. Frace, J. L. DeRisi, Q. Chen, D. Wang, D. D. Erdman, T. C. Peret, C. Burns, T. G. Ksiazek, P. E. Rollin, A. Sanchez, S. Liffick, B. Holloway, J. Limor, K. McCaustland, M. Olsen-Rasmussen, R. Fouchier, S. Gunther, A. D. Osterhaus, C. Drosten, M. A. Pallansch, L. J. Anderson, and W. J. Bellini. 2003. Characterization of a novel coronavirus associated with severe acute respiratory syndrome. Science300:1394-1399.
    OpenUrlAbstract/FREE Full Text
  291. 291.
    Rowe, T., G. Gao, R. J. Hogan, R. G. Crystal, T. G. Voss, R. L. Grant, P. Bell, G. P. Kobinger, N. A. Wivel, and J. M. Wilson. 2004. Macaque model for severe acute respiratory syndrome. J. Virol.78:11401-11404.
    OpenUrlAbstract/FREE Full Text
  292. 292.↵
    Ruan, Y. J., C. L. Wei, A. L. Ee, V. B. Vega, H. Thoreau, S. T. Su, J. M. Chia, P. Ng, K. P. Chiu, L. Lim, T. Zhang, C. K. Peng, E. O. Lin, N. M. Lee, S. L. Yee, L. F. Ng, R. E. Chee, L. W. Stanton, P. M. Long, and E. T. Liu. 2003. Comparative full-length genome sequence analysis of 14 SARS coronavirus isolates and common mutations associated with putative origins of infection. Lancet361:1779-1785.
    OpenUrlCrossRefPubMedWeb of Science
  293. 293.↵
    Saijo, M., S. Morikawa, S. Fukushi, T. Mizutani, H. Hasegawa, N. Nagata, N. Iwata, and I. Kurane. 2005. Inhibitory effect of mizoribine and ribavirin on the replication of severe acute respiratory syndrome (SARS)-associated coronavirus. Antivir. Res.66:159-163.
    OpenUrlPubMedWeb of Science
  294. 294.
    Saijo, M., T. Ogino, F. Taguchi, S. Fukushi, T. Mizutani, T. Notomi, H. Kanda, H. Minekawa, S. Matsuyama, H. T. Long, N. T. Hanh, I. Kurane, M. Tashiro, and S. Morikawa. 2005. Recombinant nucleocapsid protein-based IgG enzyme-linked immunosorbent assay for the serological diagnosis of SARS. J. Virol. Methods125:181-186.
    OpenUrlCrossRefPubMedWeb of Science
  295. 295.
    Sainz, B., Jr., E. C. Mossel, W. R. Gallaher, W. C. Wimley, C. J. Peters, R. B. Wilson, and R. F. Garry. 2006. Inhibition of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) infectivity by peptides analogous to the viral spike protein. Virus Res.120:146-155.
    OpenUrlCrossRefPubMed
  296. 296.↵
    Seto, W. H., D. Tsang, R. W. Yung, T. Y. Ching, T. K. Ng, M. Ho, L. M. Ho, and J. S. Peiris. 2003. Effectiveness of precautions against droplets and contact in prevention of nosocomial transmission of severe acute respiratory syndrome (SARS). Lancet361:1519-1520.
    OpenUrlCrossRefPubMedWeb of Science
  297. 297.
    Shao, P. L., P. R. Hsueh, L. Y. Chang, C. Y. Lu, C. L. Kao, Y. P. Chiang, H. Y. Huang, F. Y. Huang, C. Y. Lee, L. J. Chang, T. C. Wu, and L. M. Huang. 2005. Development of immunoglobulin G enzyme-linked immunosorbent assay for the serodiagnosis of severe acute respiratory syndrome. J. Biomed. Sci.12:59-64.
    OpenUrlCrossRefPubMed
  298. 298.
    Shi, X., E. Gong, D. Gao, B. Zhang, J. Zheng, Z. Gao, Y. Zhong, W. Zou, B. Wu, W. Fang, S. Liao, S. Wang, Z. Xie, M. Lu, L. Hou, H. Zhong, H. Shao, N. Li, C. Liu, F. Pei, J. Yang, Y. Wang, Z. Han, X. Shi, Q. Zhang, J. You, X. Zhu, and J. Gu. 2005. Severe acute respiratory syndrome associated coronavirus is detected in intestinal tissues of fatal cases. Am. J. Gastroenterol.100:169-176.
    OpenUrlCrossRefPubMed
  299. 299.
    Shi, Y., Y. Yi, P. Li, T. Kuang, L. Li, M. Dong, Q. Ma, and C. Cao. 2003. Diagnosis of severe acute respiratory syndrome (SARS) by detection of SARS coronavirus nucleocapsid antibodies in an antigen-capturing enzyme-linked immunosorbent assay. J. Clin. Microbiol.41:5781-5782.
    OpenUrlAbstract/FREE Full Text
  300. 300.↵
    Simmons, G., D. N. Gosalia, A. J. Rennekamp, J. D. Reeves, S. L. Diamond, and P. Bates. 2005. Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry. Proc. Natl. Acad. Sci. USA102:11876-11881.
    OpenUrlAbstract/FREE Full Text
  301. 301.↵
    Simmons, G., J. D. Reeves, A. J. Rennekamp, S. M. Amberg, A. J. Piefer, and P. Bates. 2004. Characterization of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) spike glycoprotein-mediated viral entry. Proc. Natl. Acad. Sci. USA101:4240-4245.
    OpenUrlAbstract/FREE Full Text
  302. 302.↵
    Snijder, E. J., P. J. Bredenbeek, J. C. Dobbe, V. Thiel, J. Ziebuhr, L. L. Poon, Y. Guan, M. Rozanov, W. J. Spaan, and A. E. Gorbalenya. 2003. Unique and conserved features of genome and proteome of SARS-coronavirus, an early split-off from the coronavirus group 2 lineage. J. Mol. Biol.331:991-1004.
    OpenUrlCrossRefPubMedWeb of Science
  303. 303.↵
    So, L. K., A. C. Lau, L. Y. Yam, T. M. Cheung, E. Poon, R. W. Yung, and K. Y. Yuen. 2003. Development of a standard treatment protocol for severe acute respiratory syndrome. Lancet361:1615-1617.
    OpenUrlCrossRefPubMedWeb of Science
  304. 304.↵
    Song, H. D., C. C. Tu, G. W. Zhang, S. Y. Wang, K. Zheng, L. C. Lei, Q. X. Chen, Y. W. Gao, H. Q. Zhou, H. Xiang, H. J. Zheng, S. W. Chern, F. Cheng, C. M. Pan, H. Xuan, S. J. Chen, H. M. Luo, D. H. Zhou, Y. F. Liu, J. F. He, P. Z. Qin, L. H. Li, Y. Q. Ren, W. J. Liang, Y. D. Yu, L. Anderson, M. Wang, R. H. Xu, X. W. Wu, H. Y. Zheng, J. D. Chen, G. Liang, Y. Gao, M. Liao, L. Fang, L. Y. Jiang, H. Li, F. Chen, B. Di, L. J. He, J. Y. Lin, S. Tong, X. Kong, L. Du, P. Hao, H. Tang, A. Bernini, X. J. Yu, O. Spiga, Z. M. Guo, H. Y. Pan, W. Z. He, J. C. Manuguerra, A. Fontanet, A. Danchin, N. Niccolai, Y. X. Li, C. I. Wu, and G. P. Zhao. 2005. Cross-host evolution of severe acute respiratory syndrome coronavirus in palm civet and human. Proc. Natl. Acad. Sci. USA102:2430-2435.
    OpenUrlAbstract/FREE Full Text
  305. 305.↵
    Spiegel, M., A. Pichlmair, E. Muhlberger, O. Haller, and F. Weber. 2004. The antiviral effect of interferon-beta against SARS-coronavirus is not mediated by MxA protein. J. Clin. Virol.30:211-213.
    OpenUrlCrossRefPubMed
  306. 306.
    Stadler, K., A. Roberts, S. Becker, L. Vogel, M. Eickmann, L. Kolesnikova, H. D. Klenk, B. Murphy, R. Rappuoli, S. Abrignani, and K. Subbarao. 2005. SARS vaccine protective in mice. Emerg. Infect. Dis.11:1312-1314.
    OpenUrlPubMedWeb of Science
  307. 307.↵
    St. John, R. K., A. King, D. de Jong, M. Bodie-Collins, S. G. Squires, and T. W. Tam. 2005. Border screening for SARS. Emerg. Infect. Dis.11:6-10.
    OpenUrlCrossRefPubMedWeb of Science
  308. 308.↵
    Stroher, U., A. DiCaro, Y. Li, J. E. Strong, F. Aoki, F. Plummer, S. M. Jones, and H. Feldmann. 2004. Severe acute respiratory syndrome-related coronavirus is inhibited by interferon-alpha. J. Infect. Dis.189:1164-1167.
    OpenUrlCrossRefPubMedWeb of Science
  309. 309.↵
    Su, D., Z. Lou, F. Sun, Y. Zhai, H. Yang, R. Zhang, A. Joachimiak, X. C. Zhang, M. Bartlam, and Z. Rao. 2006. Dodecamer structure of severe acute respiratory syndrome coronavirus nonstructural protein nsp10. J. Virol.80:7902-7908.
    OpenUrlAbstract/FREE Full Text
  310. 310.↵
    Su, T. P., T. C. Lien, C. Y. Yang, Y. L. Su, J. H. Wang, S. L. Tsai, and J. C. Yin. 2007. Prevalence of psychiatric morbidity and psychological adaptation of the nurses in a structured SARS caring unit during outbreak: a prospective and periodic assessment study in Taiwan. J. Psychiatr. Res.41:119-130.
    OpenUrlCrossRefPubMed
  311. 311.↵
    Subbarao, K., J. McAuliffe, L. Vogel, G. Fahle, S. Fischer, K. Tatti, M. Packard, W. J. Shieh, S. Zaki, and B. Murphy. 2004. Prior infection and passive transfer of neutralizing antibody prevent replication of severe acute respiratory syndrome coronavirus in the respiratory tract of mice. J. Virol.78:3572-3577.
    OpenUrlAbstract/FREE Full Text
  312. 312.↵
    Sui, J., W. Li, A. Murakami, A. Tamin, L. J. Matthews, S. K. Wong, M. J. Moore, A. S. Tallarico, M. Olurinde, H. Choe, L. J. Anderson, W. J. Bellini, M. Farzan, and W. A. Marasco. 2004. Potent neutralization of severe acute respiratory syndrome (SARS) coronavirus by a human mAb to S1 protein that blocks receptor association. Proc. Natl. Acad. Sci. USA101:2536-2541.
    OpenUrlAbstract/FREE Full Text
  313. 313.
    Sui, J., W. Li, A. Roberts, L. J. Matthews, A. Murakami, L. Vogel, S. K. Wong, K. Subbarao, M. Farzan, and W. A. Marasco. 2005. Evaluation of human monoclonal antibody 80R for immunoprophylaxis of severe acute respiratory syndrome by an animal study, epitope mapping, and analysis of spike variants. J. Virol.79:5900-5906.
    OpenUrlAbstract/FREE Full Text
  314. 314.
    Sung, J. J., A. Wu, G. M. Joynt, K. Y. Yuen, N. Lee, P. K. Chan, C. S. Cockram, A. T. Ahuja, L. M. Yu, V. W. Wong, and D. S. Hui. 2004. Severe acute respiratory syndrome: report of treatment and outcome after a major outbreak. Thorax59:414-420.
    OpenUrlAbstract/FREE Full Text
  315. 315.
    Surjit, M., B. Liu, S. Jameel, V. T. Chow, and S. K. Lal. 2004. The SARS coronavirus nucleocapsid protein induces actin reorganization and apoptosis in COS-1 cells in the absence of growth factors. Biochem. J.383:13-18.
    OpenUrlCrossRefPubMedWeb of Science
  316. 316.↵
    Sutton, G., E. Fry, L. Carter, S. Sainsbury, T. Walter, J. Nettleship, N. Berrow, R. Owens, R. Gilbert, A. Davidson, S. Siddell, L. L. Poon, J. Diprose, D. Alderton, M. Walsh, J. M. Grimes, and D. I. Stuart. 2004. The nsp9 replicase protein of SARS-coronavirus, structure and functional insights. Structure12:341-353.
    OpenUrlCrossRefPubMed
  317. 317.
    Takasuka, N., H. Fujii, Y. Takahashi, M. Kasai, S. Morikawa, S. Itamura, K. Ishii, M. Sakaguchi, K. Ohnishi, M. Ohshima, S. Hashimoto, T. Odagiri, M. Tashiro, H. Yoshikura, T. Takemori, and Y. Tsunetsugu-Yokota. 2004. A subcutaneously injected UV-inactivated SARS coronavirus vaccine elicits systemic humoral immunity in mice. Int. Immunol.16:1423-1430.
    OpenUrlCrossRefPubMedWeb of Science
  318. 318.↵
    Tan, E. L., E. E. Ooi, C. Y. Lin, H. C. Tan, A. E. Ling, B. Lim, and L. W. Stanton. 2004. Inhibition of SARS coronavirus infection in vitro with clinically approved antiviral drugs. Emerg. Infect. Dis.10:581-586.
    OpenUrlCrossRefPubMedWeb of Science
  319. 319.↵
    Tan, J., L. Mu, J. Huang, S. Yu, B. Chen, and J. Yin. 2005. An initial investigation of the association between the SARS outbreak and weather: with the view of the environmental temperature and its variation. J. Epidemiol. Commun. Health59:186-192.
    OpenUrlAbstract/FREE Full Text
  320. 320.
    Tan, Y. J., B. C. Fielding, P. Y. Goh, S. Shen, T. H. Tan, S. G. Lim, and W. Hong. 2004. Overexpression of 7a, a protein specifically encoded by the severe acute respiratory syndrome coronavirus, induces apoptosis via a caspase-dependent pathway. J. Virol.78:14043-14047.
    OpenUrlAbstract/FREE Full Text
  321. 321.
    Tan, Y. J., P. Y. Tham, D. Z. Chan, C. F. Chou, S. Shen, B. C. Fielding, T. H. Tan, S. G. Lim, and W. Hong. 2005. The severe acute respiratory syndrome coronavirus 3a protein up-regulates expression of fibrinogen in lung epithelial cells. J. Virol.79:10083-10087.
    OpenUrlAbstract/FREE Full Text
  322. 322.↵
    Tang, B. S., K. H. Chan, V. C. Cheng, P. C. Woo, S. K. Lau, C. C. Lam, T. L. Chan, A. K. Wu, I. F. Hung, S. Y. Leung, and K. Y. Yuen. 2005. Comparative host gene transcription by microarray analysis early after infection of the Huh7 cell line by severe acute respiratory syndrome coronavirus and human coronavirus 229E. J. Virol.79:6180-6193.
    OpenUrlAbstract/FREE Full Text
  323. 323.↵
    Tang, L., Q. Zhu, E. Qin, M. Yu, Z. Ding, H. Shi, X. Cheng, C. Wang, G. Chang, Q. Zhu, F. Fang, H. Chang, S. Li, X. Zhang, X. Chen, J. Yu, J. Wang, and Z. Chen. 2004. Inactivated SARS-CoV vaccine prepared from whole virus induces a high level of neutralizing antibodies in BALB/c mice. DNA Cell Biol.23:391-394.
    OpenUrlCrossRefPubMedWeb of Science
  324. 324.↵
    Tang, N. L., P. K. Chan, D. S. Hui, K. F. To, W. Zhang, F. K. Chan, J. J. Sung, and Y. M. Lo. 2007. Lack of support for an association between CLEC4M homozygosity and protection against SARS coronavirus infection. Nat. Genet.39:691-692, 694-696.
    OpenUrlCrossRefPubMed
  325. 325.↵
    Tang, N. L., P. K. Chan, C. K. Wong, K. F. To, A. K. Wu, Y. M. Sung, D. S. Hui, J. J. Sung, and C. W. Lam. 2005. Early enhanced expression of interferon-inducible protein-10 (CXCL-10) and other chemokines predicts adverse outcome in severe acute respiratory syndrome. Clin. Chem.51:2333-2340.
    OpenUrlAbstract/FREE Full Text
  326. 326.↵
    Tang, X. C., J. X. Zhang, S. Y. Zhang, P. Wang, X. H. Fan, L. F. Li, G. Li, B. Q. Dong, W. Liu, C. L. Cheung, K. M. Xu, W. J. Song, D. Vijaykrishna, L. L. Poon, J. S. Peiris, G. J. Smith, H. Chen, and Y. Guan. 2006. Prevalence and genetic diversity of coronaviruses in bats from China. J. Virol.80:7481-7490.
    OpenUrlAbstract/FREE Full Text
  327. 327.
    Tangudu, C., H. Olivares, J. Netland, S. Perlman, and T. Gallagher. 2007. Severe acute respiratory syndrome coronavirus protein 6 accelerates murine coronavirus infections. J. Virol.81:1220-1229.
    OpenUrlAbstract/FREE Full Text
  328. 328.
    Tanner, J. A., B. J. Zheng, J. Zhou, R. M. Watt, J. Q. Jiang, K. L. Wong, Y. P. Lin, L. Y. Lu, M. L. He, H. F. Kung, A. J. Kesel, and J. D. Huang. 2005. The adamantane-derived bananins are potent inhibitors of the helicase activities and replication of SARS coronavirus. Chem. Biol.12:303-311.
    OpenUrlCrossRefPubMedWeb of Science
  329. 329.↵
    ter Meulen, J., A. B. Bakker, E. N. van den Brink, G. J. Weverling, B. E. Martina, B. L. Haagmans, T. Kuiken, J. de Kruif, W. Preiser, W. Spaan, H. R. Gelderblom, J. Goudsmit, and A. D. Osterhaus. 2004. Human monoclonal antibody as prophylaxis for SARS coronavirus infection in ferrets. Lancet363:2139-2141.
    OpenUrlCrossRefPubMedWeb of Science
  330. 330.
    Timani, K. A., L. Ye, L. Ye, Y. Zhu, Z. Wu, and Z. Gong. 2004. Cloning, sequencing, expression, and purification of SARS-associated coronavirus nucleocapsid protein for serodiagnosis of SARS. J. Clin. Virol.30:309-312.
    OpenUrlCrossRefPubMed
  331. 331.↵
    To, K. F., J. H. Tong, P. K. Chan, F. W. Au, S. S. Chim, K. C. Chan, J. L. Cheung, E. Y. Liu, G. M. Tse, A. W. Lo, Y. M. Lo, and H. K. Ng. 2004. Tissue and cellular tropism of the coronavirus associated with severe acute respiratory syndrome: an in-situ hybridization study of fatal cases. J. Pathol.202:157-163.
    OpenUrlCrossRefPubMedWeb of Science
  332. 332.↵
    Towler, P., B. Staker, S. G. Prasad, S. Menon, J. Tang, T. Parsons, D. Ryan, M. Fisher, D. Williams, N. A. Dales, M. A. Patane, and M. W. Pantoliano. 2004. ACE2 X-ray structures reveal a large hinge-bending motion important for inhibitor binding and catalysis. J. Biol. Chem.279:17996-18007.
    OpenUrlAbstract/FREE Full Text
  333. 333.
    Traggiai, E., S. Becker, K. Subbarao, L. Kolesnikova, Y. Uematsu, M. R. Gismondo, B. R. Murphy, R. Rappuoli, and A. Lanzavecchia. 2004. An efficient method to make human monoclonal antibodies from memory B cells: potent neutralization of SARS coronavirus. Nat. Med.10:871-875.
    OpenUrlCrossRefPubMedWeb of Science
  334. 334.↵
    Tripet, B., M. W. Howard, M. Jobling, R. K. Holmes, K. V. Holmes, and R. S. Hodges. 2004. Structural characterization of the SARS-coronavirus spike S fusion protein core. J. Biol. Chem.279:20836-20849.
    OpenUrlAbstract/FREE Full Text
  335. 335.↵
    Tsai, L. K., S. T. Hsieh, C. C. Chao, Y. C. Chen, Y. H. Lin, S. C. Chang, and Y. C. Chang. 2004. Neuromuscular disorders in severe acute respiratory syndrome. Arch. Neurol.61:1669-1673.
    OpenUrlCrossRefPubMedWeb of Science
  336. 336.↵
    Tsang, K. W., P. L. Ho, G. C. Ooi, W. K. Yee, T. Wang, M. Chan-Yeung, W. K. Lam, W. H. Seto, L. Y. Yam, T. M. Cheung, P. C. Wong, B. Lam, M. S. Ip, J. Chan, K. Y. Yuen, and K. N. Lai. 2003. A cluster of cases of severe acute respiratory syndrome in Hong Kong. N. Engl. J. Med.348:1977-1985.
    OpenUrlCrossRefPubMedWeb of Science
  337. 337.↵
    Tseng, C. T., C. Huang, P. Newman, N. Wang, K. Narayanan, D. M. Watts, S. Makino, M. M. Packard, S. R. Zaki, T. S. Chan, and C. J. Peters. 2007. Severe acute respiratory syndrome coronavirus infection of mice transgenic for the human angiotensin-converting enzyme 2 virus receptor. J. Virol.81:1162-1173.
    OpenUrlAbstract/FREE Full Text
  338. 338.↵
    Tu, C., G. Crameri, X. Kong, J. Chen, Y. Sun, M. Yu, H. Xiang, X. Xia, S. Liu, T. Ren, Y. Yu, B. T. Eaton, H. Xuan, and L. F. Wang. 2004. Antibodies to SARS coronavirus in civets. Emerg. Infect. Dis.10:2244-2248.
    OpenUrlCrossRefPubMedWeb of Science
  339. 339.↵
    van der Hoek, L., K. Pyrc, M. F. Jebbink, W. Vermeulen-Oost, R. J. Berkhout, K. C. Wolthers, P. M. Wertheim-van Dillen, J. Kaandorp, J. Spaargaren, and B. Berkhout. 2004. Identification of a new human coronavirus. Nat. Med.10:368-373.
    OpenUrlCrossRefPubMedWeb of Science
  340. 340.↵
    Varia, M., S. Wilson, S. Sarwal, A. McGeer, E. Gournis, E. Galanis, and B. Henry. 2003. Investigation of a nosocomial outbreak of severe acute respiratory syndrome (SARS) in Toronto, Canada. CMAJ169:285-292.
    OpenUrlAbstract/FREE Full Text
  341. 341.↵
    Vincent, M. J., E. Bergeron, S. Benjannet, B. R. Erickson, P. E. Rollin, T. G. Ksiazek, N. G. Seidah, and S. T. Nichol. 2005. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol. J.2:69.
    OpenUrlCrossRefPubMed
  342. 342.↵
    Vogt, T. M., M. A. Guerra, E. W. Flagg, T. G. Ksiazek, S. A. Lowther, and P. M. Arguin. 2006. Risk of severe acute respiratory syndrome-associated coronavirus transmission aboard commercial aircraft. J. Travel Med.13:268-272