T cells contribute to disease severity during coxsackievirus B4 infection |
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| Authors: | Ramsingh A I Lee W T Collins D N Armstrong L E |
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| Affiliation: | Wadsworth Center, New York State Department of Health, Albany, New York 12201-2002, USA. arlene.ramsingh@wadsworth.org |
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| Abstract: | By using a model of coxsackievirus B4-induced disease, the question of whether tissue damage is due to the virus or to immune-mediated mechanisms was addressed. Both viral replication and T-cell function were implicated in contributing to the severity of disease. Three stages (I to III) of disease, which correspond to periods of high viral titers, low viral titers, and no infectious virus, have been identified. Stage I disease is considered to be primarily the result of viral replication. Immunopathological mechanisms appear to contribute to the severity of stage II and III disease. To investigate the role of T cells in contributing to the severity of disease, viral infection in CD8 knockout (ko) mice and CD4 ko mice was analyzed. CD8 T-cell responses appear to be beneficial during early, viral disease but detrimental in later disease when viral titers are diminishing. CD4 ko mice, unlike the parental strain, survived infection. Viral replication was lower in the CD4 ko mice. Was survival due to decreased viral replication or to the lack of T-helper-cell function? To investigate further the role of T helper cells in contributing to tissue damage, viral infection in two additional ko strains (interleukin-4 [IL-4] ko and gamma interferon ko strains) was examined. A clear correlation between viral replication and the outcome of infection was not observed. The absence of IL-4, which may influence T-helper-cell subset development, was advantageous during early viral disease but deleterious in later disease. The results suggest that T-cell-mediated immunity is both beneficial and detrimental during coxsackievirus B4 infection.The group B coxsackieviruses, comprising six serotypes (B1 to B6), have been implicated in a variety of diseases such as pancreatitis, type I insulin-dependent diabetes mellitus, myocarditis, and myositis (16, 24, 25, 30). The broad spectrum of diseases associated with the group B viruses reflects the existence of strains, with various degrees of virulence, within a serotype. Although there is a great deal of information on the biochemical, biophysical, and genetic characteristics of the picornaviruses, the mechanisms by which these RNA viruses cause disease are poorly understood. An ongoing question that remains to be resolved is whether tissue damage is due solely to the virus, to immunopathological mechanisms, or to a combination of both. Evidence supporting an immunopathological mechanism during coxsackievirus B3 (CVB3) infection implicates different effector cells such as CD8 T cells (10), CD4 T cells (1, 10), autoantibody-producing B cells (19, 31), and natural killer cells (9). In addition, the type of T-helper-cell response is critical in determining pathogenicity in a myocarditis model (11).To study the intricate virus-host relationship, we have developed a mouse model of CVB4-induced disease. Using two serologically indistinguishable variants of the B4 serotype, CB4-P and CB4-V, we have shown that the development of mild versus severe disease is dependent on the infecting viral strain (3). The molecular determinants of virulence of CB4-V have been identified. A threonine residue at position 129 of VP1 is a major determinant of virulence (2). An arginine residue at position 16 of VP4 also influences virulence but to a lesser extent than Thr-129 of VP1 (26).Regardless of the host’s genetic background, the CB4-P variant induces a transient inflammation of the pancreas (pancreatitis) which is followed by repair of the damaged tissues. However, the CB4-V variant induces a severe pancreatitis that can progress to chronic disease, which results in extensive and irreversible destruction of the pancreas. CB4-V infection is also lethal in some strains of mice. The outcome of infection, in B10 strains, is determined by a locus within the major histocompatibility complex (MHC) (23). During CB4-V infection, pancreatic tissue damage is probably due to a combination of mechanisms, including viral cytolysis, autodigestion by pancreatic enzymes, and immunopathology.In this study, we examined the role of the immune system in contributing to disease during infection with the virulent variant, CB4-V. The approach involved analyzing viral infection in immunologically deficient, knockout (ko) strains of mice. We showed the following: (i) CD8 T-cell responses can be beneficial during early, viral disease but detrimental during later disease; (ii) CD4 T cells contribute to the severity of disease during viral infection; (iii) the absence of interleukin-4 (IL-4) is advantageous during early viral disease but deleterious in later disease; and (iv) the outcome of viral infection can be altered by depletion of specific cellular subsets and by neutralization of specific cytokines. |
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