Abstract
Interferon (IFN)-gamma is an important component of the immune response to viral infections that can have a role both in controlling virus replication and inducing inflammatory damage. To determine the role of IFN-gamma in fatal alphavirus encephalitis, we have compared the responses of wild type C57BL/6 (WTB6) mice with mice deficient in either IFN-gamma (GKO) or the alpha-chain of the IFN-gamma receptor (GRKO) after intranasal infection with a neuroadapted strain of sindbis virus. Mortalities of GKO and GRKO mice were similar to WTB6 mice. Both GKO and GRKO mice had delayed virus clearance from the brain and spinal cord, more infiltrating perforin+ cells and lower levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 mRNAs than WTB6 mice. However, inflammation was more intense in GRKO mice than WTB6 or GKO mice with more infiltrating CD3+ T cells, greater expression of major histocompatibility complex-II and higher levels of interleukin-17A mRNA. Fibroblasts from GRKO embryos did not develop an antiviral response after treatment with IFN-gamma, but showed increases in TNF-alpha, IL-6, CXCL9 and CXCL10 mRNAs although these increases developed more slowly and were less intense than those of WTB6 fibroblasts. These data indicate that both GKO and GRKO mice fail to develop an IFN-gamma-mediated antiviral response, but differ in regulation of the inflammatory response to infection. Therefore, GKO and GRKO cannot be considered equivalent when assessing the role of IFN-gamma in CNS viral infections.
Highlights
Fibroblasts from GRKO embryos did not develop an antiviral response after treatment with IFN-gamma, but showed increases in tumor necrosis factor (TNF)-alpha, IL-6, CXCL9 and CXCL10 mRNAs these increases developed more slowly and were less intense than those of wild type C57BL/6 (WTB6) fibroblasts
Interferon (IFN)-gamma is an important component of the immune response to viral infections that can be produced by natural killer (NK), NKT and gamma/delta T cells early in infection and by CD4+ and CD8+ T cells later during the adaptive immune response
IFN-gamma has the potential for roles both in inducing an antiviral response and in regulating the immune response
Summary
Interferon (IFN)-gamma is an important component of the immune response to viral infections that can be produced by natural killer (NK), NKT and gamma/delta T cells early in infection and by CD4+ and CD8+ T cells later during the adaptive immune response. SINV causes rash and arthritis in humans, but infects neurons in mice and provides a model system for study of the pathogenesis of encephalomyelitis. Avirulent strains of SINV (e.g. AR339, TE) result in CNS infection from which the mice recover [18,19] and the process of virus clearance and recovery is dependent on local production of IFN-alpha/beta, antiviral antibody and IFN-gamma [3,20,21,22]. NSV, a neuroadapted strain of SINV, was derived by passage of AR339 in mouse brain [23] and causes fatal encephalomyelitis after intracerebral or intranasal infection of C57BL/6 (B6) mice [16,17,24,25]
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