VIRAL INHIBITION OF HOST DEFENSES

这项研究的长期目标是确定病毒感染的机制 抑制寄主对感染的防御。此信息将 增强我们对宿主防御机制的了解，以及它们的 对健康和疾病的贡献。 痘病毒家族包括人类中一些最致命的 病原体。在某种程度上，这些病毒的致病作用是 它们对抗宿主抵抗感染的能力。牛痘病毒， 一种与天花病毒密切相关的病毒，编码约200 蛋白质，其中许多与哺乳动物的病毒抑制有关 对抗病毒感染的免疫过程。尤其是这种病毒 有效抑制炎症过程。由于这一特性，它 为调查这些过程提供了一个独特的系统。这 系统已经使我们能够识别出五种病毒细胞因子反应 修饰物：一种白细胞介素1-β转换酶的抑制物，a 可溶性白介素1受体、可溶性分泌型肿瘤坏死因子受体 类型和一种类似于配体结合部分的可溶性蛋白 CD30。我们的结果表明，牛痘病毒编码额外的细胞因子- 影响非特异性寄主防御的反应调节剂和抑制物， 包括炎症过程和细胞凋亡，以及特异性免疫 防御。 这项研究的具体目的是鉴定和表征病毒 有助于病毒抑制宿主防御的机制，最初 强调那些有助于以下方面的机制： 1)细胞因子对感染反应的修饰。 2)抑制病毒感染细胞的凋亡。 3)抑制炎症反应。 对有效抑制痘病毒的机制的了解 对感染的宿主防御应有助于新的 与传染病相关的各种疾病的治疗， 炎症性疾病、自身免疫性疾病、癌症和器官移植 不同的，不同的。

The long-term goal of this study is to identify mechanisms of viral inhibition of host defenses against infection. This information will enhance our understanding of the mechanisms of host defenses, and their contributions to health and disease. The poxvirus family includes some of the most virulent of all human pathogens. In part, the pathogenic effects of these viruses result from their abilities to counter host defenses against infection. Cowpox virus, a virus closely related to smallpox virus, encodes about two hundred proteins, many of which are involved in the viral inhibition of mammalian immune processes countering virus infection. In particular, this virus effectively inhibits inflammatory processes. Because of this property, it provides a unique system for the investigation of these processes. This system has already enabled us to identify five viral cytokine-response modifiers: an inhibitor of the interleukin-1-beta converting enzyme, a soluble interleukin-1 receptor, soluble secreted TNF receptors of two types, and a soluble protein similar to the ligand-binding portion of CD30. Our results suggest that cowpox virus encodes additional cytokine- response modifiers and inhibitors affecting non-specific host defenses, including inflammatory processes and apoptosis, and specific immune defenses. The specific aims of this study are to identify and characterize viral mechanisms contributing to viral inhibition of host defenses, with initial emphasis upon those mechanisms contributing to: 1) The modification of cytokine responses to infection. 2) The inhibition of apoptosis in virus-infected cells. 3) The inhibition of inflammatory responses. Knowledge of the mechanisms involved in the effective poxviral inhibition of host defenses against infection should assist the development of new therapies for a variety of conditions associated with infectious diseases, inflammatory diseases, autoimmune diseases, cancers, and organ transplantat n.