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Clinical Microbiology Reviews, October 2001, p. 821-835, Vol. 14, No. 4
Department of Pathology, University of
Michigan Medical School, Ann Arbor, Michigan
0893-8512/01/$04.00+0 DOI: 10.1128/CMR.14.4.821-835.2001
Molecular Machinations: Chemokine Signals in
Host-Pathogen Interactions
SUMMARY
INTRODUCTION
CHEMOKINES
CHEMOKINE RECEPTORS
CHEMOKINE EVOLUTION
CHEMOKINES IN DEVELOPMENT AND HOMEOSTASIS
Lymphoid Tissue Development and Leukocyte Homing
Hematopoiesis
CYTOKINE-CHEMOKINE NETWORKS
CHEMOKINES AND INFECTIONS
Bacterial Infections
Fungal Infections
Protozoal Infections
Helminthic Infections
Viral Infections
CHEMOKINE EVASION BY VIRUSES
CLOSING REMARKS
REFERENCES
SUMMARY
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Chemokines and their G-protein-coupled receptors represent an ancient and complex system of cellular communication participating in growth, development, homeostasis and immunity. Chemokine production has been detected in virtually every microbial infection examined; however, the precise role of chemokines is still far from clear. In most cases they appear to promote host resistance by mobilizing leukocytes and activating immune functions that kill, expel, or sequester pathogens. In other cases, the chemokine system has been pirated by pathogens, especially protozoa and viruses, which have exploited host chemokine receptors as modes of cellular invasion or developed chemokine mimics and binding proteins that act as antagonists or inappropriate agonists. Understanding microbial mechanisms of chemokine evasion will potentially lead to novel antimicrobial and anti-inflammatory therapeutic agents.
INTRODUCTION
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No area of study reflects the benefit of the molecular biologic and informatics revolution better than the field of chemokine research. The first of these small protein molecules (8 to 17 kDa) with potent neutrophil chemotactic activity, now known as interleukin-8(IL-8), was cloned just over a decade ago (116). Since that time, by exploiting expressed sequence tag libraries, more than 40 human chemokines and nearly as many murine homologues have been described. The term "chemokine" was applied to these molecules since their principal biologic activity was considered to be chemotactic, i.e., directing cellular movement along concentration gradients during inflammatory responses. While chemokines are only one class of many types of known chemotactins that span the molecular spectrum from lipids to nucleotides, they stand out because of their molecular stability and target cell specificity. In recent years it has become apparent that their function extends beyond simply attracting leukocytes to sites of inflammation. Evidence indicates that chemokines participate in organ development, angiogenesis, angiostasis, homeostatic leukocyte recirculation, and immune regulation. Since a number of recent reviews have discussed these topics in detail (21, 25, 84, 86, 93, 99, 103, 110, 143, 151, 176, 183), they will be covered only briefly in this review. Instead, after providing some background, the discussion will focus on chemokines as they relate to different microbial infections and provide recent insight into the dynamic contest between host and pathogen to take advantage of chemokine function.
CHEMOKINES
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Chemokines are a homologous superfamily of relatively small
proteins ranging from 8 to 17 kDa that probably arose through duplication and modification of an ancestral gene. The superfamily of
chemokines is subclassified on the basis of the arrangement of cysteine
residues located in the N-terminal region of these molecules. These are
designated C, CC, CXC, and CXXXC, where C represents the number of
N-terminal region cysteine residues and X represents the number of
intervening amino acids. The CXC subfamily is sometimes further
classified into ELR and non-ELR types on the basis of the presence or
absence of a triplet amino acid motif (Glu-Leu-Arg) that precedes the
first cysteine amino acid residue of the primary structure of these
chemokines. The presence of this motif imparts angiogenic function to
this class of chemokines, while the ELR-negative chemokines have
angiostatic properties (83). Table
1 provides a listing of known human
chemokines and their nearest mouse homologues, along with a new
systematic nomenclature proposed by Zlotnik and Yoshie
(183).
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Virtually every tissue and cell type tested to date can be induced to secrete chemokines. While a single cell type, like mononuclear phagocytes, may produce a variety of chemokines, there is known tissue-restricted expression of certain chemokines, suggesting that some chemokines have organ-specific functions.
CHEMOKINE RECEPTORS
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Not surprisingly, great effort has been directed toward gaining an
understanding of the mechanisms of chemokine signal transduction. It is
well established that chemokines exert their effect through guanosine
nucleotide-protein-coupled receptors (GPCR), which are among a
superfamily (potentially over 1,000 members, representing 1% of the
genome) of related receptors that are involved in transducing a broad
spectrum of extracellular stimuli such as hormones, neurotransmitters, chemokines, odorants, and light (14). In general, the
chemokine receptors are between 320 and 380 amino acids in length and
show significant sequence homology. A list of human chemokine
receptors, their murine homologues, and their cellular distribution is
presented in Table 2.
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Like all known GPCR, the chemokine receptors have seven transmembrane
hydrophobic domains with three intracellular and three extracellular
hydrophilic loops. A potentially glycosylated extracellular amino-terminal region is involved in chemokine binding, while the
intracellular carboxy-terminal region is involved in G-protein linking
and is subject to regulatory phosphorylation. Chemokine receptor
activation begins with extracellular ligand binding, which triggers
interaction with the intracellular quiescent GDP-bearing trimeric
G-proteins (99, 109, 179). This results in exchange of GDP
for GTP, causing the G-protein to dissociate into G-alpha and
G-beta/gamma subunits. The latter subunit in turn activates enzymes such as phospholipase C and phosphoinositide-3-kinase, which
convert phosphotidylinositol-4,5-diphosphate (IP2) into phosphotidylinositol-1,4,5-triphosphate (IP3) and
diacylglycerol (DAG). IP3 stimulates the influx of
calcium ions, and DAG activates protein kinase C (PKC) isoforms.
The intracellular environment is thus prepared for a cascade of
phosphorylation events involving a series of kinases (e.g.,
mitogen-activated protein kinase, protein typsine kinase) and
small GTPases (e.g., Ras and Rho) that ultimately effect cellular functions such as adhesion, chemotaxis,
degranulation, and respiratory burst (48, 69, 106). An
interesting aspect of chemokine receptor biology was the finding that
different receptors may be linked to different G-proteins, which in
themselves represent a large class of signal transduction proteins
(3, 90). Differential linkage of chemokine receptors could
imply that cellular effector functions can be differentially induced.
The basic structural characteristics and activation of chemokine
receptors are shown in Fig. 1.
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A mention should be made of chemokine receptor desensitization and regulation. After ligation, chemokine receptors may be internalized and then degraded or recycled, leaving the membrane temporarily unresponsive to further ligand stimulation. In addition, as alluded to above, the C-terminal region contains target residues that may be phosphorylated by GPCR kinases, which allows the binding of regulatory molecules called arrestins, which cause uncoupling and desensitization (23, 56). Another manner by which the signaling can be regulated is by direct inactivation of the G-protein activity by GTPases, known as RGS (regulators of G-protein signaling) proteins (46).
Chemokine receptors were first described on leukocytes. Subsequently,
they have been found on endodermal, mesenchymal, ectodermal, and
neuroectodermal cells. Thus, chemokines may participate in the
growth and migration of epithelial cells of the skin (88, 118), digestive (51, 123) and reproductive
(182) tracts, and neuronal and glial cells of the central
nervous system (70). Analysis of chemokine receptor
expression by leukocytes has revealed that receptor subtypes are
expressed to differing degrees by different cell types, thereby
dictating their responsiveness to the various chemokines. For example,
neutrophils strongly express CXCR1 and CXCR2, making them most
responsive to ELR+ CXC ligands, whereas eosinophils appear
more responsive to CCR3 ligands. An important aspect of these analyses
is evidence suggesting that chemokine receptor expression is subject to
cytokine-mediated regulation (16, 28, 101, 112, 133),
which permits fine-tuning of cellular responses based on organ location
and host immune status. Still more intriguing is evidence
indicating that chemokine receptor expression by T lymphocytes changes
with maturational state, a notion promoted by Sallusto et al.
(150-152). As shown in Fig.
2, in this model naîve
CD4+ T cells express receptors CCR7 and CXCR4,
allowing their normal recirculation through lymphoid tissues. On
encountering antigen, the primed T cell enters a T-helper (Th) cell
memory stage and expresses a particular complement of receptors
depending on whether it is of the Th1 or Th2 subtype. The former
express CCR1, CCR2, CCR5, and CXCR3, while the latter selectively
express CCR2, CCR3, CCR4, and CCR8. Further activation of the memory
subtypes results in expression of CCR7 and CXCR5 to facilitate movement
to secondary lymphoid tissues. This model is based in large part on in
vitro studies of T-cell receptor transgenic cells and T-cell clones; it
has yet to be fully tested in vivo and will no doubt undergo modification. In any event, the model offers hope of developing stage-specific receptor targeted interventional therapies.
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CHEMOKINE EVOLUTION
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In phylogenetic terms, directed cellular movement in response to
external stimuli is an ancient biologic response. Indeed, G-protein-mediated migratory responses are demonstrable in protozoa (126). Comparative amino acid sequence analysis of mammals
and primitive vertebrates indicate that the CXC and CC groups of
chemokines diverged from an ancestral gene even before the divergence
of the various orders of mammals and probably before the emergence of
vertebrates (78, 124). Thus, chemokines represent a very ancient system of cellular communication that has undergone extensive refinement over evolutionary time Fig. 3.
For example, the CC group of chemokines has diverged into at least
three major clusters. The first group is represented by macrophage
inflammatory protein 1
MIP-1, MIP-1
, and RANTES
(mostly CCR1 and CCR5 ligands), the second is represented by the
monocyte chemotactic proteins and eotaxin (mostly CCR2 and CCR3
ligands), and the third is represented by I-309 (CCR8 ligand).
Interestingly, the C-type chemokines fall into a separate but related
cluster, while the CCR4 ligand, MDC, defines an independent group that
diverged early from the ancestral chemokine gene. In a similar fashion,
the major groups of CXC and CC GPCR branched early from an ancestral
gene before the divergence of mammalian orders and appear to have
coevolved with their chemokine ligands (64), but the mode
of receptor gene evolution was possibly different from that of the
chemokines (78). As more chemokines and receptors are
defined in various species, further phylogenetic analyses may provide
critical information that will allow us to match the evolutionary
appearance of immune functions with that of chemokines and their
receptors.
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CHEMOKINES IN DEVELOPMENT AND HOMEOSTASIS
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Initially, the study of chemokines focused on their role in the pathogenesis of inflammation, but in recent years it has become apparent that these molecules participate in organ system development and homeostasis. Transcripts for particular chemokines are constitutively expressed in many tissues under normal physiologic conditions. These presumably are participating in physiologic events. The breadth of involvement remains to be fully determined, but studies to date have established roles in lymphoid tissues, bone marrow, and vascular tissues.
Lymphoid Tissue Development and Leukocyte Homing
The thymus is a critical organ for T-lymphocyte development, and
it expresses transcripts for several chemokines with
lymphocyte-attracting properties, such as CCL25 (TECK), CCL17 (TARC),
CCL21 (SLC), CCL19 (ELC), and CXCL12 (SDF-1), which have been
implicated in the function of this organ (26, 29, 87, 174,
177). Thymic T-cell development involves several migration steps
from the influx of immature pre-T cells to movement from the cortex to
the medulla to the blood as they achieve maturity. Chemokines are
thought to direct this process, through a combination of changing
chemokine receptor expression by different stages of maturing T cells
and microenvironmental chemokine production. For example, the chemokine TECK is produced by thymic dendritic cells and is a selective chemotactin for immature T cells (174). Thus, TECK could
direct the influx of immature T cells as they begin their maturation process in the thymus.
As in the thymus, there are many migration events associated with lymph node function that involve the movement of lymphocytes, dendritic cells, and macrophages through cortical germinal centers and medullary sinuses. Chemokines such as SLC, BLC, MDC, PARC, TARC, and LARC appear to be involved in the formation of secondary lymphoid tissues and lymphocyte recirculation. In particular, the CXCR5 ligand CXCL13 (B lymphocyte chemokine [BLC]), is important to B-cell mobilization (39-41) while the CCR7 ligand CCL21 (secondary lymphoid tissue chemokine [SLC]) may play a significant role in naîve T-cell migration to lymph nodes (178). SLC is expressed by specialized postcapillary high endothelium of the lymphoid tissues and is active on naîve T cells, dendritic cells, and, to a lesser extent, B cells (168). Mice lacking the SLC gene display abnormal lymph node T-cell homing (67) and, complementarily, transgenic ectopic expression of SLC by pancreatic islet cells results in the local organization of lymphoid tissue (54). Thus, SLC participates in both the development and maintenance of peripheral lymphoid tissues. Other chemokines, like MDC (79) and LARC (47), produced in lymph node microenvironments probably contribute to the migration of memory T cells and dendritic cells to cortical follicles.
Hematopoiesis
Regulation of blood-forming elements is another potentially
important function of chemokines. In this regard, CXCR4 ligands such as
CXCL12 (SDF-1) appear necessary for normal hematopoiesis since mice
with disruption of the CXCR4 gene display defects in B lymphopoiesis
and myelopoiesis. Specifically, stromal cell-derived factor (SDF-1) is
a product of bone marrow stromal cells and is involved in mobilizing
the emigration of hematopoietic precursors to the marrow during
embryogenesis (1, 2).
Interestingly, chemokines appear to influence bone marrow
function independently of their chemotactic activity. A large
number of CC and CXC chemokines have direct myelosuppressive activity on bone marrow cell proliferation when tested in vitro and in vivo (21, 22). One of the best studied of the
myelosuppressive chemokines is MIP-1, which causes a
dose-dependent inhibition of cycling status and decreases
the absolute numbers of bone marrow progenitor cells when
administered to mice (38). This physiologic function
was further demonstrated in mice with knockout of CCR1, a major
MIP-1 receptor, which displayed enhanced lineage-committed myeloproliferation and leukocyte mobilization to the blood
(20). The myelosuppressive chemokines could
potentially be exploited as adjuvant agents in the
chemotherapeutic treatment of leukemias, where it is beneficial to
protect residual normal marrow precursors by temporarily inducing a
nonproliferative state.
CYTOKINE-CHEMOKINE NETWORKS
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Before the role of chemokines in specific infectious states is
discussed, the interactions of chemokines and cytokines should be
mentioned. It has long been recognized that many infectious agents and
their components are potent inducers of cytokines such as interleukins,
tumor necrosis factors (TNF), and interferons (IFN), which appear to
contribute to microbial resistance (157). It is not
surprising that recent efforts have been directed toward exploring the
capacity of cytokines to regulate chemokine expression and vice versa.
Among cytokines, TNF-, an important product of macrophages, is an
especially potent inducer of chemokine synthesis in a number of cell
types, including neutrophils, fibroblasts, smooth muscle cells, and
endothelial and epithelial cells (72, 104, 125, 166, 169).
In vivo depletion of TNF- in a model of mycobacterial granuloma
formation indicated that it provided support to a broad spectrum of
chemokines (135). Some chemokines such as MIG and
IP-10 are more selectively induced by IFN-
(55). However, under circumstances of infection, cytokines probably likely
synergize with each other and with microbial elements to regulate
chemokine production. Interestingly, Th1- and Th2-derived cytokines can
have antagonistic effects on chemokines. For example, the Th2-related
cytokines IL-4 and IL-13 induce monocyte-derived chemokine (MDC)
and C10 production in macrophages, but this is inhibited by the Th1
cytokine IFN- (17, 128). Cytokine regulation of
chemokines also appears to be target cell specific, as illustrated by
the observation that IL-4 and IL-13 strongly induce monocyte chemotactic protein 1 (MCP-1) in endothelial cells but inhibit production in epithelial cells (63, 91, 139). As discussed below, many microbial products can directly evoke chemokines, but the
spectrum and degree of chemokines produced in response to infectious
agents will be modified in part by cytokines produced during host
innate and acquired immune responses. As illustrated in Fig.
4, chemokines are probably produced in
stages following a microbial insult, resulting in a cascade of
amplification.
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CHEMOKINES AND INFECTIONS
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The greatest focus of chemokine study has been their relationship
to infection and inflammation, no doubt because of the central role of
leukocyte responses in these conditions. Numerous papers on these
topics have been published in recent years, and certain major themes
are beginning to emerge. First, chemokine expression has been detected
in association with virtually every microbial infection examined (Table
3). Second, different classes of
chemokines may aid host resistance to different microbial agents.
Specifically, in an environment with pathogens ranging from viruses to
multicellular parasites, specific chemokines may be required to elicit
the most effective response by mobilizing appropriate leukocyte
subpopulations and effector functions. Examples would include
neutrophils in response to staphylococci, eosinophils in response to
helminths, or cytotoxic T cells in response to viruses. Third,
chemokines can be undermined and exploited by pathogenic microbes that
neutralize, mimic, and disrupt their activity. The remainder of this
review will present some of the important findings in these areas,
beginning with a discussion of the role of chemokines in specific types of microbial infections.
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Bacterial Infections
Mounting evidence supports the notion that chemokines play an
important role in innate immunity to bacteria. In a murine model of
peritoneal sepsis, Matsukawa et al. demonstrated roles for MCP-1 and
MDC in protecting the host from lethality (114, 115). MCP-1 is indirectly responsible for recruitment of neutrophils by way
of leukotriene induction, whereas MDC is important to activation and
mobilization of peritoneal macrophages. A recent exciting discovery by
Krijgsveld et al. (89) seems to further expand the
functional role of chemokines in innate immunity. In a survey of human
platelet -granule proteins, truncated variants of CXC chemokines
were isolated and found to be directly bactericidal for Bacillus
subtilis, Escherichia coli, Staphylococcus
aureus, and Lactococcus lactis, as well as fungicidal
for Cryptococcus neoformans (89). Thus,
chemokine-like molecules may represent a novel class of antimicrobial
agents for therapeutic exploitation.
It is well known that resistance to many gram-positive and
gram-negative bacterial infections is dependent on the efficient mobilization of polymorphonuclear neutrophilic leukocytes. These phagocytic cells are normally mobilized within minutes to hours of
tissue disruption and consequently play a crucial role in preventing dissemination of infectious bacteria. Many bacteria release products such as formylated peptides, which are directly chemotactic for neutrophils by way of GPCR. In addition to this adaptation,
host-generated chemokines provide further amplification to the
recruitment of neutrophils. These cells are highly responsive to
ELR+ CXC chemokines (8), which are potently
induced in host cells by bacterial and bacterial products such as
S. aureus, endotoxin, peptidoglycan, or Pseudomonas
aeruginosa coenzyme S (53, 175). Indeed, using cDNA
array analysis, Wang et al. monitored the expression of 600 genes in
human monocytes stimulated with bacterial products and found that genes
encoding the chemokines IL-8, MIP-2, MIP-1, and MIP-1
represented the most strongly induced of the cytokine genes
(175). Of these, IL-8 and MIP-2 are both potent
ELR+ CXC neutrophil chemotactins. The circumstantial
evidence suggesting a role for these CXCR1 and CXCR2 ligands in
bacterial resistance has been further supported by direct
demonstration. Tsai et al. reported that neutralization of the CXCR2
receptor in mice caused striking mortality due to P. aeruginosa pneumonia that was associated with reduced neutrophil
recruitment and bacterial clearance (171). In an animal
model of corneal P. aeruginosa keratitis, Kernaki et al.
showed a critical role for MIP-2 in neutrophil recruitment (85). An important role for epithelial cell-derived IL-8
has been demonstrated in the intestine. Teleologically, it is
reasonable to predict that epithelial cells residing at the interface
between the host and a potentially microbe-infested environment should have the capacity to secrete chemokines, and many investigators have
shown this to be the case (107, 144, 156, 163, 164, 167).
IL-8 is expressed strongly by gut epithelial cells. In a rabbit model
of Shigella flexneri infection, Sansonetti et al. demonstrated that neutralization of IL-8 decreased the influx of
neutrophils into the gut lamina propria and attenuated the severity of
epithelial lesions (153). However, bacteria displayed increased transepithelial translocation and growth in the lamina propria with increased passage into the mesenteric blood. Thus, IL-8
was essential in preventing bacterial invasion but did so at the
expense of epithelial bystander damage by activated neutrophils.
In addition to gram-positive and -negative bacteria, other types of
bacteria and bacterium-related microorganisms have the capacity to
induce host chemokines. Consistent with the prominent interstitial
leukocyte recruitment associated with Mycoplasma infection,
this organism induces the expression of the neutrophil-attracting CXC
chemokines. IL-8 and growth-related oncogene GRO-,
as well as the mononuclear leukocyte-attracting CC chemokines
MCP-1, MIP-1, and MIP-1 (44, 80, 160). A major
stimulating agent was mycoplasma membrane-derived macrophage-activating
lipopeptide 2 (MALP-2), which appears to be a primary molecular element
recognized by the host.
Chemokine production may not be beneficial in all types of bacterial
infections. The spirochetal etiologic agent of Lyme disease, Borrelia burgdorferi, strongly stimulated MIP-1
expression as well as IL-8, GRO-, MCP-1, and RANTES
expression in human monocytes, but it is unclear if these products
effectively promote the elimination of this organism
(162). In fact, in Borrelia infection the
chemokines may prove harmful by contributing to tissue damage and
chronic arthritis. In a similar vein, Yoneyama et al.
(181) demonstrated that fulminant hepatitis induced by
Propionibacterium acnes infection and endotoxin was
dependent on TARC, a CCR4 ligand that was responsible for hepatic
recruitment of host CCR4+ CD4+ T cells. Immune
cell recruitment was associated with lethal hepatic failure.
Bacteria that manifest predominantly as chronic intracellular
infections, such as Mycobacteria and Listeria
spp., provide special difficulty for the host since chemokines may not
be consistently effective in eliminating these agents. It is recognized
that mycobacterial organisms induce chemokine production. Compared with
controls, bronchoalveolar lavage fluid from patients with active
pulmonary tuberculosis contained increased levels of RANTES,
MCP-1, and IL-8 (147). In vitro studies indicate that the
degree of chemokine production may vary with the bacterial strain and
is not necessarily related to resistance (138).
Macrophages are key targets of intracellular bacterial colonization.
Ligands of CCR2, like MCP-1, can promote macrophage activation and
contribute to macrophage recruitment during the T-cell-mediated
granulomatous inflammation in response to mycobacterial antigens
(19). However, with suboptimal activation of intracellular
killing mechanisms, chemokine-mediated inflammation may not be
sufficient for protective immunity, which may rely more on cytokines
such as IFN- and TNF-, as suggested by Orme and Cooper
(129). In this model, macrophage-rich, chemokine-mediated granulomas are generated but represent a primitive, less optimal sequestration response when intracellular bacterial destruction fails.
As with mycobacteria, Listeria infection induces a spectrum
of chemokines including MCP-1, MIP-1, MIP-2, RANTES,
IP-10, and IL-8 (9, 58). However, in contrast to
mycobacteria, Listeria-induced chemokines such as MIP-1
and MCP-1 may contribute more significantly to bacterial elimination,
since interference with these chemokines did result in impaired
elimination of organisms (35, 94). Specifically, unlike
wild-type CD8+ T cells, those from MIP-1 knockout mice
failed to confer protection when adoptively transferred to
Listeria-infected recipients, and similarly disruption of
the MCP-1 receptor, CCR2, profoundly compromised the capacity of mice
to eliminate this organism. Thus, the relative contribution of
chemokines may vary significantly with the virulence of the organism
and its adaptive countermeasures.
Fungal Infections
A role for chemokines in fungal resistance was first suggested by
Huffnagle et al., who demonstrated by chemokine neutralization that
MIP-1 was required during the efferent phase of Th1-cell-mediated immunity to the yeast-like fungus C. neoformans in mice
(77). Specifically, MIP-1 promoted the recruitment of
phagocytic effectors, most notably neutrophils and macrophages, into
the lungs. It was subsequently demonstrated, using MIP-1 knockout
mice, that resistance to central nervous system cryptococcal
infection was also dependent on MIP-1 (76).
Likewise, mice with knockout of CCR1, a MIP-1 receptor, showed
impaired resistance to C. neoformans (62). Another chemokine, TCA-3, also appears to contribute to cryptococcal immunity, but this was shown to act indirectly by inducing mononuclear cell chemoattractants MIP-1 and MCP-1 (50).
Recent studies of chemokines in cryptococcal infection of human cells
have revealed interesting findings. Incubation of primary human
endothelial cells with C. neoformans did not induce
chemokine synthesis but resulted in differential inhibition of
cytokine-induced IL-8, IP-10, and MCP-1 (122). Chemokine
suppression may be an important virulence factor for C. neoformans and may explain the often sparse inflammation
associated with opportunistic infections. For example, mice infected
intratracheally with a highly virulent strain of C. neoformans demonstrated active proliferation of organisms in the
alveolar spaces and a poor cellular inflammatory response (82). This was associated with little or no production
of MCP-1, RANTES, MIP-1, MIP-1, and IP-10. This
could be reversed by administration of IL-12, a Th1- and natural killer
(NK)-cell-stimulatory agent, which induced the synthesis of these
chemokines along with cellular infiltration involving histiocytes and
CD4+ lymphocytes. A study by Huang and Levitz, showed that
infection of human peripheral blood mononuclear cells with either
Cryptococcus or Candida caused the release of
MIP-1, MIP-1 and RANTES (75). However,
this study also showed that production was not impaired in mononuclear
cells from immunocompromised patients with human immunodeficiency virus
(HIV) infection, thus pointing to the critical role of Th cells in
ultimate fungal resistance. Taken together, the studies suggest
that chemokines are important to the mobilization of leukocytes but
that Th1-cell-derived factors are needed to efficiently kill and
eliminate fungal organisms.
Chemokines also contribute to resistance in nonyeast fungal
infections. The ELR+ CXC chemokines MIP-2 and KC/GRO
were induced in response to intratracheal administration of conidia of
Aspergillis fumigatus (117).
Antibody-mediated neutralization of the CXC chemokine receptor CXCR2 resulted in invasive aspergillosis that was
associated with reduced lung neutrophil influx and a marked increase in
mortality. In contrast, animals provided with constitutive
lung-specific transgenic expression of KC/GRO were resistant to the
organism, with reduced mortality and a lower fungal burden in the
lungs. Thus, CXCR2 ligands appear to be critical mediators of host
resistance to invasive A. fumigatus.
Another aspect of Aspergillis infection is the potential development of chronic aspergillosis associated with allergic responses that can result in hypersensitivity pneumonitis and pulmonary fibrosis. This condition may normally be kept in check by CCR2 ligands such as MCP-1, since CCR2 knockout mice display exacerbated Aspergillus hypersensitive responses and lung damage (12). Ironically, other types of chemokines may ultimately contribute to the lung damage. Specifically, the late-stage fibrotic remodeling of lung airways caused by Aspergillus hypersensitivity is in part mediated by CCR1 ligands, since disruption of the CCR1 gene ameliorates this pathology (13).
Protozoal Infections
The relationship of protozoa to chemokines was discovered by Horuk
et al. in 1993, when it was reported that the CXC chemokines IL-8 and
GRO could block binding of the malarial agent Plasmodium knowlesi to the erythrocyte Duffy blood group antigen
(74). It has since been established that the Duffy
antigen, a receptor for P. knowlesi and P. vivax,
is a promiscuous chemokine receptor also known as DARC (Duffy
antigen-related chemokine receptor). DARC is expressed by erythrocytes,
capillary endothelial cells, renal collecting-duct epithelial cells,
lung alveoli, and cerebellar Purkinje cells (134).
Analogous to HIV, some Plasmodium species have exploited
chemokine receptors as a means of penetrating host cell membranes.
Interestingly, DARC is also among the spectrum of chemokine receptors
used by HIV-1, allowing erythrocytes to potentially act as a retroviral
reservoir (95).
While host chemokine receptors may abet malarial infection, it is
unclear if the chemokine ligands promote elimination. Human P. falciparum infection is associated with IL-8 and MIP-1 release into the circulation (24). Circumstantially, the
chemokines are at their highest circulating levels when parasites are
at their lowest, but a direct antimalarial effect has yet to be
established. However, it is conceivable that chemokine blockade of
receptors could inhibit cellular penetration by malarial parasites,
thereby limiting subsequent rounds of cell penetration.
Leishmaniasis, another well-studied protozoan infection, is also
associated with chemokine induction that appears to promote immunity.
Human monocytes infected with promastigotes of the causative agent
of cutaneous leishmaniasis, Leishmania major, display rapid induction of MCP-1 and IL-8 (7). Similarly, mouse bone
marrow-derived macrophages exposed to L. major promastigotes
displayed rapid and transient expression of transcripts of MCP-1 and
GRO-, but MIP-1, C10, and RANTES were not induced
(136). Of the induced chemokines, MCP-1 was involved in
macrophage recruitment to the cutaneous lesions and microbial killing
(121). Further evidence for chemokine-mediated resistance
to L. major was demonstrated in mice with knockout of CCR2
(MCP-1 receptor), which displayed defective dendritic cell migration to
the spleen and subsequent impaired Th1-cell-mediated immunity
(155).
Helminthic Infections
Adaptive resistance to parasitic worms is a complex biologic
issue. Many parasites have learned to fall short of rapidly killing their host and are often difficult to eliminate, as a result of either
modulated host immunity or direct evasive measures used by the
parasite. When generated, the specific mode of parasite-directed immunity is dependent on the particular maturation stage of the parasite and its primary site of infestation. For example,
tissue-penetrating stages of parasites generally induce destructive
interstitial inflammatory responses whereas intestinal parasites often
induce expulsive responses in the gut in addition to some degree of
inflammation. Both Th1 (IFN--mediated) and Th2 (IL-4, IL-5, and
IL-13-mediated) immune responses participate in various antihelminthic
reactions, but particular attention has been paid to the role of the
latter. It is widely recognized that Th2-mediated responses,
characterized by eosinophil-rich inflammation, immunoglobulin E (IgE)
and IgA production, and mast cell degranulation, are commonly induced during parasitic infections. Moreover, this complex of responses seems
to be directed toward worm elimination since it involves the delivery
of helminthicidal proteins and stimulation of intestinal expulsion. Not
surprisingly, chemokines appear to participate in various aspects of
this response.
Evidence suggests that Th2 cytokines elicited by helminth antigens are often associated with strong elicitation of CC chemokines such as MCP-1, MCP-3, MCP-5 and eotaxin, which potentially recruit helminthicidal leukocytes (32, 98, 102, 120, 146, 154). Specifically, since inflammatory responses to helminth parasites often involve eosinophils, it has raised the possibility that helminth infections elicit a specific complement of chemokines designed to recruit eosinophils. Indeed, CCR3 agonists, which are potent chemotactins for eosinophils, are commonly induced during Th2 responses (36, 120, 146, 169). Moreover, using specific anti-CCR3 antibodies, Grimaldi et al. showed this receptor to be important to eosinophil mobilization during Nippostrongylus brasiliensis infection of mice (66). Thus, hosts have probably adapted specific chemokine responses to deal with helminth parasites that are induced or augmented by Th2-cell-derived cytokines.
Chemokines appear to have regulatory effects during immune
responses to helminths. Infection with the etiologic agent of river blindness, Onchocerca volvulus, causes a destructive
corneal inflammation (keratitis) that is probably related to the
host's attempt to kill the worms. Treatment with the helminthicidal
agent ivermectin induces parasite destruction that is associated with
the production of IL-8, eotaxin, and RANTES (36,
37). Eotaxin correlated with eosinophil mobilization, but
RANTES was seemingly tempering eosinophil recruitment. A
similar cross-regulatory effect of RANTES was shown in the
response to egg antigens of Schistosoma mansoni that was
possibly related to direct RANTES-mediated inhibition of
Th2-cell-derived IL-4 production (31). Interestingly,
RANTES is among a group of chemokines, including MIP-1 and
MIP-1, which appear to be more selectively associated with Th1
responses (158). Therefore, the balance of Th1- and
Th2-associated chemokines and cytokines generated during
helminth infection probably dictates the final nature of the host
response. For example, in a murine model of onchocercal
antigen-elicited keratitis, exogenously administered IL-12, an
IFN--promoting chemokine, impaired Th2 cytokines while augmenting
the local production of chemokines (IP-10, MIP-1, MIP-1,
MCP-1/JE, RANTES, and eotaxin) and exacerbating corneal damage (131). Thus, the Th2 component may protect
bystander host tissues from excessive Th1-mediated damage. In
a similar fashion, this cross-regulatory effect of the Th2
response associated with helminth infection has been demonstrated to
temper coexistent Th1-mediated responses to other microbes,
specifically blunting responses to Helicobacter pylori
bacteria and bacillus Calmette-Guérin vaccination (59,
111).
Viral Infections
Much attention has been directed at the relationship of viral
infection and chemokines. This is especially true since the discovery
that HIV utilizes chemokine receptors for attachment to and penetration
of host cells. Since this topic has been widely reviewed (11, 33,
71, 73, 100, 142, 145), it will not be discussed further here.
Rather, the role of chemokines in antiviral responses will be
presented. Like other microbes, viruses represent a diverse class of
microorganisms varying in their target tissue preferences and ultimate
pathogenic manifestations. The optimal response mechanisms used by the
host must therefore also vary. Viral immunity usually employs induction
of IFNs, antibody-mediated neutralization, cell-mediated cytotoxicity,
or combinations of these mechanisms. Cytotoxicity would
potentially involve chemokines for local recruitment of immune effector
cells such as cytotoxic lymphocytes and NK cells. Due to cytopathic
effects, virally infected cells probably provide the initital source of
chemokines that initially recruit and activate inflammatory leukocytes,
which in turn begin a cascade of events involving induction of
cytokines such as IFN- and TNF- that further amplify chemokine
synthesis and leukocyte recruitment with ultimate destruction of
virally infected cells. Unfortunately, the latter is sometimes
associated with significant bystander damage and potentially permanent
organ impairment, e.g., hepatitis-induced cirrhosis. Since their
survival depends on viable target tissues, it is in the interest of
viruses to undermine host resistance, at least until another host can be infected. Recent reports suggest that eluding chemokine function is
one mode used by viruses to achieve this end.
A survey of the literature reveals numerous reports of various modes of
chemokine evasion used by viruses (discussed below), but there is
surprisingly limited evidence demonstrating a direct role for
chemokines in viral resistance. Studies of influenza virus and
respiratory syncitial virus infection have provided some insights in
this regard. Chemokines are clearly produced during these infections.
Upper respiratory tract secretions contain increased levels of IL-8,
MCP-1, MIP-1, MIP-1, and RANTES in response to
influenza virus or respiratory syncytial virus infection that correlate
statistically with symptoms and virus release (18, 60, 127,
170). Interestingly, cotaxin, which is constitutively expressed
at low levels in respiratory epithelial cells, is also augmented by
influenza virus infection and has been shown to potentially contribute
to virus-associated asthmatic responses (81). Mice with
knockout of the MIP-1 gene had reduced pneumonitis and delayed clearance of influenza virus compared to controls, suggesting that this
chemokine promotes but is not essential to viral resistance (34). However, in a model of paramyxovirus infection,
either MIP-1 or CCR1 knockout resulted in reduced pneumonitis and
impaired viral clearance (49). A more recent analysis of
influenza virus-infected mice with CCR2 (MCP-1 receptor) or CCR5
(RANTES, MIP-1 receptor) knockout revealed increased
mortality in the latter that was associated with exacerbated
pneumonitis whereas the former showed reduced pathology but augmented
viral titers (43). These studies illustrate the delicate
balance that must be achieved for viral resistance. While chemokines
may promote the elimination of infected cells, they also can contribute
to inflammation-related morbidity.
The double-edged nature of the chemokine sword is also apparent in
herpesvirus infections of MIP-1 knockout mice. In a model of murine
hepatic cytomegalovirus infection, MIP-1 was needed for NK cell
recruitment to the liver and early virus elimination (149). However, in experimental herpes simplex
virus-induced keratitis, MIP-1-evoked inflammation led to blindness
but failed to contribute to viral elimination (172).
Another approach that has been used to test the role of chemokines and cytokines in viral resistance is by genetic engineering of poxviruses to express chemokine and cytokine genes. Such engineered viruses become the source of active mediators upon infection of the host. These studies demonstrated the contribution of MIG and IP-10 to host leukocyte mobilization, but the chemokines lacked direct antipoxvirus activity (137).
CHEMOKINE EVASION BY VIRUSES
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While more studies are needed to explore the role of chemokines in viral resistance, it would seem from a teleological viewpoint that it is in the survival interest of viruses to exploit host cells while minimizing the host inflammatory responses. For viruses with limited cytopathic effects, such mechanisms may also be of benefit to the host by minimizing bystander organ damage. Therefore, it is not surprising that viruses have acquired numerous mechanisms to undermine multiple host mediators (for a recent review, see reference 5), but the present discussion will focus on those involving chemokines. It is generally considered that viral chemokine-related elements were derived from acquired host genes during the course of evolution. Therefore, DNA viruses such as herpesviruses and poxviruses appear to be particularly well endowed with regard to chemokine evasive mechanisms, but it should be recognized that this field is still emerging and that undoubtedly other viral and nonviral infectious agents will be found to have developed chemokine countermeasures.
Chemokine function can be undermined in several ways: (i) production of
chemokine mimics that act as receptor antagonists, (ii) production of
chemokine mimics that act as inappropriate agonists, (iii) production
of receptor mimics, and (iv) synthesis of binding proteins that
neutralize chemokine activity. Table 4
provides a listing of some of these viral agents and their known
activities. As will be illustrated by the discussion below, the precise
physiologic function of many of these factors is unknown and largely
speculative.
|
Viral chemokine evasive mechanisms may be related to the different
modes of infection and dissemination utilized by viral species and
their subtypes. Human herpesvirus 8 (HHV-8), an agent associated with
Kaposi's sarcoma, is the source of a number of chemokine mimics,
vMIP-I, MIP-II, and MIP-III (42, 161, 165). It is
particularly intriguing that several groups have reported that vMIP
chemokines have agonistic interactions with CCR8 or CCR4, chemokine
receptors expressed by Th2 cells (42, 52, 161, 165). This
activity has provoked the notion that HHV-8 may interfere with the
Th1/Th2 immune balance, specifically impeding Th1 (IFN--dominated)
antiviral responses. However, in conflicting reports, Chen et al.
(30) showed anti-inflammatory effects of vMIP-II in an rat
model of glomerulonephritis and Luttichau et al. (105)
demonstrated vMIP-II to be a broad-spectrum chemokine receptor
antagonist, suggesting that HHV-8 directly inhibited chemokine
function. In addition, the latter group showed that the skin-infecting
Molluscum contagiosum poxvirus produced a highly selective CCR8
antagonist, raising the possibility that this virus tempers antiviral
immunity by impeding the recruitment of dendritic cells bearing CCR8.
Chemokines associated with herpesviruses (HHV-6 and cytomegalovirus) and HIV-1 (4, 57, 108, 132, 148, 184) have agonist activity that appears to promote the recruitment of leukocytes that can serve as a means of viral dissemination. Specifically, it was shown that induced mutations of viral chemokine genes resulted in viral forms causing reduced inflammation and impaired capacity for dissemination (57, 148). In the case of the chemokine-like agonist Tat, produced during HIV-1 infection, not only did it have monocyte chemoattractant properties but also it could promote the expression of CXCR4 in bystander CD4+ cells (159). Consequently, the host T cells would be more susceptible to infection by HIV types utilizing CXCR4 as a coreceptor.
Among the viral chemokine receptors, ORF74 is a functional GPCR of HHV-8 with significant homology to the high-affinity IL-8 receptor, and it appears to promote cell growth. Particularly, it appears to promote the formation of Kaposi's sarcoma-like angioproliferative tumors, as demonstrated by transgenic expression in mice (141, 180). This activity is fully consistent with the known angiogenic properties of the ELR+ CXC chemokines like IL-8 (10, 45), and it may serve as a means of viral proliferation or survival. Other described chemokine receptors and binding proteins appear to behave primarily as promiscuous chemokine "sponges," reducing local chemokine concentrations and presumably limiting inflammation (see Table 4 for references). As these viral products become better characterized, they may ultimately serve as the basis of novel therapeutic anti-inflammatory agents.
CLOSING REMARKS
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For over a decade, chemokine research has been an exciting and rapidly burgeoning field. We are just beginning to understand the meaning of this ancient mode of chemical communication that has been expanded and refined during evolution to participate in virtually every aspect of physiology. With regard to the interaction of host and pathogen, chemokines are undoubtedly central to immunity, serving both as the sparks that initiate responses to infection and as the fuel that feeds subsequent inflammation. The importance of the chemokine system to host defense is reflected by its extensive built-in redundancy and the elaborate mechanisms used by microbes to undermine or exploit its function. A detailed knowledge of this system will probably provide novel means of manipulating host immunity to promote efficient elimination of pathogens and temper organ-damaging inflammatory conditions.
FOOTNOTES
* Mailing address: Pathology and Laboratory Medicine 113, Veterans Affairs Health Care System, 2215 Fuller Rd., Ann Arbor, MI 48105. Phone: (734) 761-7947. Fax: (734) 761-5037. E-mail: schensue{at}med.umich.edu.
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Clinical Microbiology Reviews, October 2001, p. 821-835, Vol. 14, No. 4
0893-8512/01/$04.00+0 DOI: 10.1128/CMR.14.4.821-835.2001
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