Poxvirus Immune Evasion Mechanisms

痘病毒包括一些危险的新出现或重新出现的病原体以及 一些有希望的传染病和癌症疫苗载体。他们是独一无二的， 病毒编码大量的蛋白质，这些蛋白质专门用于逃避宿主 免疫反应。这些蛋白质包括分泌的细胞因子抑制剂以及 免疫信号传导的细胞内抑制剂或抗病毒因子。我们项目的长期目标是 是揭示痘病毒免疫逃避的机制，这将揭示痘病毒免疫逃避的基本机制。 病毒与宿主相互作用的原理，并为疫苗的开发提供知识 和抗病毒药物我们上一个资助期的重点是一种分泌型痘病毒白细胞介素-18 （IL-18）结合蛋白（IL-18 BP），其阻止IL-18诱导IFN-γ产生。我们 我们的工作非常富有成效，并实现了所有具体目标。此外，我们还发现， 牛痘病毒（VACV）的两种I型干扰素（IFN）的细胞内抑制剂，K1和C71，2.这是 一个令人兴奋的发现，因为K1和C7是痘病毒复制所必需的宿主范围因子 但它们的作用机制一直是个谜。我们假设 K1和C7是痘病毒复制所必需的，因为它们抑制了一个关键的 IFN诱导的抗病毒途径。因此，揭示K1和C7的作用机制 不仅揭示了痘病毒宿主嗜性的分子基础， 对痘病毒的防御机制。在下一个资助周期，我们建议跟进 在K1和C7上的发现，并追求以下目标。 目标1。基于C7家族晶体结构的VACV C7结构功能分析 蛋白质。 目标2.确定K1和C7靶向的宿主抗病毒因子。 目标3。确定K1和C7在复制能力中的体内作用， VACV的免疫原性。

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-¿ 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.