RSV INDUCED PATTERN OF CYTOKINE EXPRESSION AND DISEASE

呼吸道合胞病毒（RSV）是导致 婴儿严重下呼吸道疾病， 流感是造成非洲国家死亡率和发病率过高的原因之一， 老年人，并在骨髓移植单位引起流行病 在大多数情况下死亡。 适当的治疗和 疫苗是不可用的，部分原因是由于独特的 RSV诱导疾病的免疫学特征。 福尔马林灭活整体 病毒疫苗（FI-RSV）不能预防感染， 与增强的疾病有关。 来自小鼠模型的数据和证据 人类研究表明，选择性诱导CD 4 + T细胞， 具有2型细胞因子表达模式的淋巴细胞（显性IL-4 生产）的FI-RSV疫苗的基础上， 病 婴儿严重RSV细支气管炎也与以下因素相关： 2型免疫反应。 这项建议的主要目的是 定义RSV促进相关免疫应答的机制 具有2型细胞因子产生模式。 具体的救济是： 1)定义RSV G糖蛋白促进 嗜酸性粒细胞增多、Th 2样免疫应答和增强的疾病，和2） 定义IL-4延迟病毒清除、抑制 CD 8 + CTL诱导，并促进增强的RSV诱导的疾病。 的 RSV G的独特抗原特性将使用重组 表达膜锚定G、分泌G或 两者的产量相等。 我们将定义G结构的作用 和抗原加工事件对IL-5的IL-4非依赖性诱导 和嗜酸性粒细胞。 机制 IL-4对CD 8 + CTL诱导的抑制作用将使用 我们实验室构建的重组牛痘病毒， 共表达RSV M2蛋白和单个细胞因子。 的 拟议的研究将确定病毒和宿主因素负责 RSV感染后的免疫应答模式和疾病表达 感染 它们将提高我们对病毒如何 导致疾病，以及疫苗诱导的免疫反应如何调节， 将对制定预防性战略的新战略产生直接影响， RSV的疫苗和免疫治疗剂。

Respiratory Syncytial Virus (RSV) is the most important cause of severe lower respiratory tract disease in infants, rivaling influenza as a cause of excess mortality and morbidity in the elderly, and causing epidemics in bone marrow transplant units with fatality in the majority of cases. Adequate therapy and vaccines are not available, in part because of the unique immunologic features of RSV-induced disease. Formalin-inactivated whole virus vaccine (FI-RSV) did not protect against Infection and was associated with enhanced disease. Data from murine models and evidence from human studies suggest that selective induction of CD4+ T lymphocytes with a Type 2 cytokine expression pattern (dominant IL-4 production) by the FI-RSV vaccine is the basis for vaccine-enhanced illness. Severe RSV bronchiolitis in infants is also associated with Type 2 immune responses. The primary objective of this proposal is to define the mechanisms by which RSV promotes immune responses associated with Type 2 pattern of cytokine production. The specific alms are to: 1) Define the mechanisms by which the RSV G glycoprotein promotes eosinophilia, Th2-like immune responses, and enhanced illness, and 2) Define the mechanisms by which IL-4 delays virus clearance, inhibits CD8+ CTL induction, and promotes enhanced RSV-induced illness. The unique antigenic properties of RSV G will be studied using recombinant vaccinia viruses that express membrane-anchored G, secreted G, or produce both in equal amounts. We will define the role of G structure and antigen processing events on the IL-4 independent induction of IL-5 and eosinophils recently discovered in our laboratory. The mechanism of IL-4 inhibition of CD8+ CTL induction will be defined using recombinant vaccinia viruses constructed in our laboratory that co-express the RSV M2 protein and individual cytokines. The proposed studies will define viral and host factors responsible for patterns of immune response and disease expression after RSV infection. They will improve our basic understanding of how viruses cause disease, and how vaccine-induced immune responses are regulated, will have direct impact on new strategies for development of preventive vaccines and immunotherapeutics for RSV.