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Department of Infectious Diseases, University of Georgia, College of Veterinary Medicine, Athens, Georgia
Correspondence and requests for reprints should be addressed to Ralph A. Tripp, College of Veterinary Medicine, Department of Infectious Diseases, University of Georgia, Athens, GA 30602. E-mail: ratripp{at}uga.edu
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ABSTRACT |
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Key Words: chemokine • cytokine • protein, suppressor of cytokine signaling • virus, respiratory syncytial
Respiratory syncytial virus (RSV) is an important viral respiratory pathogen of infants and young children worldwide infecting nearly 70% of infants in their first year of life, and most children between ages 2 and 3 (1–3). RSV may cause repeat infections throughout life, with serious complications occurring in the elderly and immunocompromised patient (3–5). RSV generally causes a mild upper respiratory tract infection; however, a substantial number of children infected with RSV may develop serious lower respiratory tract illness (LRTI) requiring hospitalization (1). RSV infection may be associated with short- and long-term morbidity and complications that include recurrent wheezing, reactive airway disease, and pulmonary function abnormalities (5, 6). Unfortunately, no safe and effective RSV vaccine is available, and few effective prophylactic or therapeutic treatments exist. Accumulating evidence suggests that the spectrum of cytokine expression associated with RSV infection affects the balance between virus elimination and disease pathogenesis, and may influence the continuum of clinical manifestations that may include bronchiolitis, pneumonia, apnea, and pulmonary function abnormalities (7–9). Understanding the cytokine response to RSV infection is required to guide vaccine and intervention strategies; however, achieving this objective is complicated. Cytokines are produced de novo by a variety of immune cell types and have a variety of activities. Cytokines may act on the cells that secrete them (autocrine), on nearby cells in the microenvironment (paracrine), or affect distant cells (endocrine). The same cytokine may be expressed by different cell types, and a single cytokine may act on several different cell types (pleiotropy) (10). In addition, cytokines may exhibit redundant activity, may act synergistically or antagonistically, and are often expressed in a cascade, that is, one cytokine stimulates its target cells to express additional cytokines (10). These features and their short half-life complicate the understanding of cytokine regulation of the immune response and disease pathogenesis associated with RSV infection.
The superfamily of cytokines have a central role in the antiviral response to RSV infection (7, 9, 11). The largest group regulates immune cell proliferation and differentiation and includes IFN-
, interleukin (IL)-2, and IL-12 (Th1-type cytokines) and IL-4, IL-5, IL-6, and IL-10 (Th2-type cytokines). Other cytokine groups include antiviral interferons (IFN-
, IFN-ß) and chemokines (C, CC, CXC, and CX3C groups) which attract and activate specific types of leukocytes to sites of infection. RSV primarily infects and replicates in the airway epithelium of the nasal passages and large and small airways in the lung, although there is mounting evidence that RSV may also infect alveolar macrophages and possibly other cell types in the lung (12, 13). The antiviral and cell-mediated immune response to RSV infection is initially orchestrated by cytokines expressed by RSV-infected airway epithelial cells and by alveolar macrophages. RSV infection of epithelial cells has been shown to lead to the activation of signaling pathways that result in the expression of host genes involved in the establishment of an antiviral state, namely, /ß interferons (IFN-/ß) (14, 15). IFN-/ß induce gene expression in neighboring cells by binding to cell surface cytokine receptors which activate the JAK-STAT signaling pathway and result in the induction of host proteins and cytokines that impair viral replication. To support viral replication, RSV has countermeasures encoded in its genome to manipulate the cytokine response. The RSV genome is composed of single-stranded negative sense RNA in which 10 mRNAs are 3' to 5' sequentially transcribed from the genome to produce 11 proteins: NS1, NS2, N, P, M, SH, G, F, M2-1. M2-2, and L. The 3'-terminal location of NS1 and NS2 genes allows these gene products to be the most abundantly expressed proteins in RSV-infected cells due to their promoter-proximal location. NS1 and NS2 genes may aid virus replication by independently and coordinately antagonizing the activity of IFN-/ß, as well as affecting the newly described antiviral cytokines IFN-
1, -2, and -3 (16, 17). In addition, our laboratory has shown that the evolutionary conserved nonglycosylated central region of the G protein contains a CX3C chemokine motif capable of interacting with the CX3C chemokine receptor, CX3CR1, antagonizing the activities of the fractalkine (the only known CX3C chemokine), and modifying trafficking of CX3CR1+ immune cells (18). CX3CR1+ cytotoxic leukocytes possess high levels of perforin and granzyme B, and preferentially exhibit chemotaxis toward fractalkine (19). Interaction of CX3CR1+ cytotoxic effector cells with membrane-bound fractalkine promotes cytotoxic effector cell migration toward secondary CC chemokines such as macrophage inflammatory protein (MIP)-1ß (19); thus, fractalkine-CX3CR1 interaction is important in recruitment of cytotoxic effector cells to sites of infection regardless of their lineage or target cell recognition. Because the RSV G protein CX3C motif can compete with fractalkine for binding to CX3CR1 and alter fractalkine-mediated responses (18), it is possible that RSV G protein can modify the response by CX3CR1+ cytotoxic leukocytes.
The immune response to primary RSV infection in humans and mice is generally characterized by a mixed Th1/Th2 cytokine response (8, 20, 21). Studies in mice have shown that a predominant Th1-type cytokine response occurs after primary infection with an RSV deletion mutant virus lacking the G and SH genes compared to infection with wild-type RSV (22). In addition, studies in mice infected with recombinant vaccinia viruses have shown that RSV F and G proteins prime different T cell responses (23, 24), and immunization with RSV G protein promotes activation of Th2 CD4+ T cells (25). The implications of these findings are that RSV F or G protein expression may modify the T cell response to infection and affect the Th1/Th2 cytokine balance. Imbalanced Th1/Th2 cytokine responses have been associated with pulmonary function abnormalities linked to RSV infection (26–28). Infants hospitalized with severe RSV disease have been shown to have reduced IFN- levels in nasopharyngeal aspirates, and reduced levels of IFN- expressed by peripheral blood mononuclear cells (29, 30). Accumulating evidence suggests that RSV may predispose for chronic pulmonary function abnormalities, for example, asthma after severe infection early in childhood (31), and asthma is a chronic respiratory disease characterized by inflammatory processes that are associated with Th2-type cytokines, for example, IL-4, IL-5, and IL-13 (27). A Th1/Th2 cytokine imbalance early in childhood may affect the development of the T cell memory repertoire, as cytokines have a critical role at several junctures in this pathway, and T cells have different cytokine requirements as they subsist.
It is well established that RSV infection of epithelial cells induces chemokine expression and that chemokines have an important role in recruiting leukocytes to areas of infection. The CC chemokines are a subgroup of chemokines that attract lymphocytes and eosinophils to sites of inflammation, and can incite inflammatory responses by inducing mediator release from eosinophils, basophils, and mast cells (32, 33). Evidence suggests that excessive release of CC chemokines at the time of RSV infection may cause severe inflammation and have an equally important role in RSV disease pathogenesis as Th2-type cytokines. In one study of infants and children less than 15 months of age either presenting to outpatient clinics or hospitalized with acute respiratory disease caused by RSV infection, high levels of CC-chemokines were associated with severe inflammation and bronchiolitis, whereas RSV infection was not associated with a clear Th2-like cytokine response (34). Two notable CC chemokines associated with RSV pathogenesis are MIP-1/CCL3 and RANTES/CCL5. Substantially higher concentrations of CCL3 and CCL5 have been found in nasopharyngeal secretions and tracheal aspirates of infants with RSV bronchiolitis compared with healthy children undergoing elective surgery (35), as well as in infants intubated because of RSV infection compared with infants intubated for nonrespiratory illnesses (36). Studies in mice comparing the chemokine response to infection with wild-type RSV or a RSV mutant lacking G and SH genes showed that G and/or SH protein expression was associated with reduced CCL2, CCL3, and CCL4 mRNA expression by bronchoalveolar lavage (BAL) cells (37). Because these CC chemokines interact with CCR1 and CCR5, chemokine receptors preferentially expressed on Th1 cells (38), these results suggest that G and/or SH protein expression may impair Th1 responses mediated by these chemokines.
Understanding the host and virus mechanisms that regulate cytokine and chemokine expression is necessary for development of RSV vaccine and intervention strategies. It is known that a number of highly inducible cytokine genes contain nuclear factor-
B (NF-B) binding sites in their proximal promoters that may be induced by RSV infection, and NF-B has been shown to be important in RSV-inducible gene expression for a number of genes with diverse functions (39, 40). NF-B–dependent genes include important members of the interferon regulatory factor (IRF) family, and IRF-1 has been shown to be required for the development of Th1-type immune responses, whereas its absence has been shown to lead to the induction of Th2-type immune responses (41). Central to the regulation of cytokine expression are the suppressors of cytokine signaling (SOCS) and cytokine-inducible SH2 protein (CIS) family of intracellular proteins. The SOCS protein family includes eight members (SOCS-1 to SOCS-7 and CIS) all sharing a central SH2 domain and a C-terminal SOCS box (42). SOCS-1 and SOCS-3 appear to be the most effective members of this family, and act as part of a negative feedback circuit involving the JAK-STAT pathway to regulate cytokine expression, particularly the IFN-induced signal cascade (43, 44). SOCS proteins also have a critical role in regulating the functional activity of T cells (45), a feature that may be exploited by viruses to alter antiviral responses. For example, overexpression of hepatitis C virus (HCV) core protein has been shown to inhibit IFN signaling and induce SOCS-3 expression, and SOCS-1 and SOCS-3 proteins have been shown to inhibit IFN-induced activation of the JAK-STAT pathway and expression of antiviral proteins such as MxA (44, 46). These data suggest that viruses may modify SOCS protein expression to manipulate the Th1/Th2 cytokine pathway and the antiviral host response. There is no direct evidence that RSV affects SOCS protein expression; however, RSV infection of human epithelial cells has been shown to inhibit the type I IFN JAK-STAT pathway (15), and accumulating evidence indicates that several RSV proteins may modify the cytokine and chemokine response to infection (7, 17). Several studies implicate the importance of IFN- signaling in maintaining the Th1/Th2 cytokine balance to RSV infection. IFN- receptor knockout mice infected with RSV exhibit increased IL-4, IL-5, and IL-13 expression and the presence of eosinophils in the lungs (47), and wild-type infected mice depleted of IFN- exhibit Th2-type cytokine driven pulmonary eosinophilia (48). Because SOCS-1 and SOCS-3 negatively regulate the IFN-induced signal cascade, and RSV NS1 and NS2 proteins inhibit the type I IFN response, it possible that RSV NS1, NS2, or other viral proteins may regulate the IFN response by affecting SOCS protein expression. This strategy may be used to reduce the efficacy of innate and acquired immune responses to infection; however, RSV modification cytokine or chemokine responses may also be a mechanism to recruit new targets for infection, or provide new niches for infection.
Several RSV disease intervention strategies have targeted Th1/Th2-type cytokines or chemokines for inhibition. These studies generally show that inhibition or knockout of cytokines or chemokines has modest or mixed effects, as most cytokines exhibit redundant activity, may act synergistically or antagonistically, and once initiated, is often expressed in a cascade (e.g., "cytokine storm"). Because SOCS proteins are differentially expressed in Th1- and Th2-type cells (49), and important in Th1/Th2 maintenance (50), preferential silencing of SOCS expression using methods such as RNAi (51) may offer a new therapeutic intervention strategy to control RSV disease pathogenesis.
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FOOTNOTES |
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Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
(Received in original form February 4, 2005; accepted in final form March 3, 2005)
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expression in peripheral blood mononuclear cells of infants with severe respiratory syncytial virus disease. Am J Respir Crit Care Med 1999;160:1263–1268.This article has been cited by other articles:
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