CHEMOKINES IN THE IMMUNE RESPONSE TO A VIRAL INFECTION

病毒性呼吸道感染在人类中会导致严重的疾病和死亡，并可能加剧哮喘等先前存在的疾病。虽然病毒发病机制的某些方面已经被广泛研究，但在病毒感染的免疫反应中调节白细胞运输的机制却知之甚少。趋化因子是一个结构相关的细胞因子超家族，被认为在白细胞运输中发挥关键作用。本研究的目的是阐明趋化因子及其受体在小鼠伽马疱疹病毒68免疫应答中的作用。感染MHV-68的小鼠会患上一种类似流感的急性呼吸道疾病。MHV-68还会导致小鼠的淋巴结肿大、脾肿大和单核细胞增多症，就像人类的爱泼斯坦-巴尔病毒一样。有趣的是，MHV-68基因组编码一个CXCR2趋化因子受体同源物，这可能在病毒的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伽马疱疹病毒中是保守的，如人类疱疹病毒8型(HHV8)，它与卡波西氏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，可能有助于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。这项工作可能对通过增强或抑制趋化因子的表达进行治疗干预具有重要意义。在拟议的研究中：1)MIP-1α、MCP-1、CCR2和CXCR2在MHV-68免疫应答中的作用将通过缺乏或过度表达这些基因的小鼠来检测，而淋巴动素、CRG-2、RANTES和MIP-1β的作用将通过这些因子的中和血清来确定。2)预先存在的变态反应性炎症对MHV-68免疫应答、病毒致病机制和趋化因子谱的影响将被确定。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)CXCR2趋化因子受体同源物在病毒致病中的作用将使用编码CXCR2同源物的基因失活的突变病毒来确定。

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.