CHEMOKINES IN THE IMMUNE RESPONSE TO A VIRAL INFECTION

病毒性呼吸道感染会导致人类严重疾病和死亡，并可能加剧哮喘等原有疾病。 虽然病毒发病机制的某些方面已被广泛研究，在病毒感染的免疫应答过程中调节白细胞运输的机制知之甚少。 趋化因子是结构相关的细胞因子的超家族，并且被认为在白细胞运输中起关键作用。 本研究旨在阐明趋化因子及其受体在小鼠γ疱疹病毒68（MHV-68）免疫应答中的作用。 感染了MHV-68的小鼠会发展出一种类似于流感的急性呼吸道疾病。 MHV-68还在小鼠中诱导淋巴结肿大、脾肿大和单核细胞增多症，就像爱泼斯坦巴尔病毒在人类中所做的那样。 有趣的是，MHV-68基因组编码CXCR 2趋化因子受体同源物，其可能在病毒发病机制中发挥作用。 这种病毒趋化因子受体在密切相关的γ疱疹病毒中是保守的，例如人类疱疹病毒8（HHV 8），其与卡波西肉瘤和某些类型的淋巴瘤的发展有关。 研究NMV-68在小鼠中的感染，可能会深入了解趋化因子及其受体在病毒引起的人类疾病中的作用。 这项工作可能有重要的意义，通过增强或抑制趋化因子的表达治疗干预。在拟议的研究中：1）MIP-1 α、MCP-1、CCR 2和CXCR 2在对MHV-68的免疫应答中的作用将通过使用这些基因缺陷或过表达的小鼠来检查，而趋化因子、Crg-2、RANTES和MIP-1 β的作用将使用这些因子的中和抗血清来确定。 2)将确定既存过敏性炎症对MHV- 68免疫应答、病毒发病机制和趋化因子谱的影响。 特定趋化因子的作用将通过使用缺乏这些趋化因子或其受体的小鼠或通过使用中和抗体来研究。 3)CXCR 2趋化因子受体同源物在病毒发病机制中的作用将使用突变病毒来确定，其中编码CXCR 2同源物的基因已经失活。

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.