CHEMOKINES IN THE IMMUNE RESPONSE TO A VIRAL INFECTION

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Viral respiratory infections cause significant disease and mortality in humans and can exacerbate pre-existing conditions such as asthma. Although certain aspects of viral pathogenesis have been studied extensively, mechanisms regulating leukocyte trafficking during the immune response to viral infection are poorly understood. Chemokines are a superfamily of structurally- related cytokines and are thought to play key roles in leukocyte trafficking. The aim of this study is to elucidate the role of chemokines and their receptors in the immune response to murine gammaherpesvirus 68 (MHV-68). Mice infected with MHV-68 develop an acute respiratory disease similar to influenza. MHV-68 also induces lymph node enlargement, splenomegaly, and mononucleosis in mice, as Epstein Barr virus does in humans. Interestingly, the MHV-68 genome encodes a CXCR2 chemokine receptor homologue which may play a role in viral pathogenesis. This viral chemokine receptor is conserved in closely-related gammaherpesviruses such as human herpesvirus 8 (HHV8) which has been implicated in the development of Kaposi's sarcoma and certain types of lymphoma. Studying NMV-68 infection in mice, may provide insight into the role of chemokines and their receptors in human disease caused by viruses. This work may have important implications for therapeutic intervention through the enhancement or inhibition of chemokine expression. In the proposed study: 1) The role of MIP-1alpha, MCP-1, CCR2 and CXCR2 in the immune response to MHV-68 will be examined by using mice deficient in, or overexpressing these genes, while the role of lymphotactin, Crg-2, RANTES, and MIP-1beta will be determined using neutralizing antisera to these factors. 2) The effect of pre-existing allergic inflammation on the immune response to MHV- 68, viral pathogenesis and the chemokine profile will be determined. The role of specific chemokines will be studied by using mice lacking these chemokines or their receptors or by using neutralizing antibodies. 3) The role of the CXCR2 chemokine receptor homologue in viral pathogenesis will be determined using a mutant virus in which the gene encoding the CXCR2 homologue has been inactivated.