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.

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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.

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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).

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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.

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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).

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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.

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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.

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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).

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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).

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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).

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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.

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