Poxvirus Immune Evasion Mechanisms

描述(申请人提供)：痘病毒包括一些危险的新出现或再次出现的病原体，以及一些有希望的传染病和癌症疫苗载体。它们在病毒中是独一无二的，因为它们编码大量专门用于逃避宿主免疫反应的蛋白质。这些蛋白质包括分泌的细胞因子抑制物以及免疫信号或抗病毒因子的细胞内抑制物。我们项目的长期目标是揭示痘病毒免疫逃避的机制，这将揭示病毒与宿主相互作用的基本原理，并为疫苗和抗病毒药物的开发提供知识。我们上一个资助期的重点是一种分泌型痘病毒白介素18(IL-18)结合蛋白(IL-18BP)，它可以阻止IL-18诱导干扰素-γ的产生。我们一直非常富有成效，实现了所有具体目标。此外，我们在痘苗病毒(VACV)中发现了两种I型干扰素的胞内抑制物，K1和C71，2。这是一个令人兴奋的发现，因为K1和C7是哺乳动物宿主复制痘病毒所必需的宿主范围因子，但它们的作用机制长期以来一直是个谜。我们假设K1和C7对于痘病毒复制是必不可少的，因为它们抑制了干扰素诱导的关键抗病毒途径。因此，揭示K1和C7的作用机制不仅将揭示痘病毒宿主趋向性的分子基础，而且还将揭示针对痘病毒的关键的先天免疫防御机制。在下一个资金周期，我们建议跟进我们在K1和C7上的发现，并追求以下目标。目的1.基于C7蛋白家族的晶体结构分析VACV C7的结构与功能。目的2.确定K1和C7靶向的宿主抗病毒因子。目的3.确定K1和C7在VACV体内复制能力和免疫原性中的作用。

DESCRIPTION (provided by applicant): Poxviruses include some dangerous emerging or re-emerging pathogens as well as some promising vaccine vectors for infectious diseases and cancers. They are unique among viruses in that they encode a large number of proteins that are dedicated to evading host immune responses. These proteins include secreted inhibitors of cytokines as well as intracellular inhibitors of immune signaling or antiviral factors. The long-term goal of our project is to uncover the mechanisms of poxvirus immune evasion, which will reveal fundamental principles about virus-host interactions and provide knowledge for the development of vaccines and antivirals. The focus of our last funding period was on a secreted poxvirus interleukin-18 (IL-18) binding protein (IL-18BP), which prevents IL-18 from inducing IFN-gamma production. We have been very productive and accomplished all the specific aims. In addition, we discovered in vaccinia virus (VACV) two intracellular inhibitors of type I interferons (IFN), K1 and C71,2. This is an exciting finding, since K1 and C7 are host-range factors essential for poxviruses replication in mammalian hosts but their mechanism of action has long been a mystery. We hypothesize that K1 and C7 are essential for poxvirus replication due to their inhibition of a critical IFN-inducible antiviral pathway. Therefore uncovering the mechanism of action of K1 and C7 will reveal not only molecular basis for poxvirus host tropism but also critical innate immune defense mechanism against poxviruses. In the next funding cycle, we propose to follow up our discoveries on K1 and C7 and pursue the following aims. Aim 1. Structure-function analysis of VACV C7 based on crystal structures of C7 family of proteins. Aim 2. Identify the host antiviral factors that are targeted by K1 and C7. Aim 3. Determine the in vivo role K1 and C7 play in replication capacity and immunogenicity of VACV.