Poxvirus Immune Evasion Mechanisms

痘病毒免疫逃避机制

• 批准号: 8632750
• 负责人: YAN XIANG
• 金额: $ 38.4万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-24 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8632750
• 关键词: Adopted; Affinity Chromatography; Antiviral Agents; Antiviral Therapy; Attenuated; Binding; Cells; Communicable Diseases; Defense Mechanisms; Development; Evolution; Family; Family member; Funding; Genes; Genetic; Goals; Homologous Gene; Immune; Immune response; In Vitro; Interferon Regulatory Factor 1; Interferon Type I; Interferon Type II; Interferons; Interleukin-18; Knowledge; Ligands; Malignant Neoplasms; Mass Spectrum Analysis; Methods; Molecular; Monkeypox virus; Mutagenesis; Pathway interactions; Plague Vaccine; Play; Population; Poxviridae; Production; Protein Family; Proteins; Role; Signal Transduction; Small Interfering RNA; Smallpox Viruses; Structure; Testing; Tropism; Ursidae Family; Vaccines; Vaccinia virus; Viral Proteins; Virus; base; crosslink; cytokine; design; follow-up; immunogenic; immunogenicity; in vivo; inhibitor/antagonist; interleukin-18 binding protein; knock-down; member; next generation; novel; pathogen; prevent; protein function; public health relevance; scaffold; vaccine development; vaccinia virus vector; vector vaccine; virus host interaction

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.

痘病毒包括一些危险的新兴或重新出现的病原体以及 一些承诺用于传染病和癌症的疫苗向量。他们在 病毒是因为它们编码了大量用于逃避宿主的蛋白质 免疫反应。这些蛋白质包括细胞因子的分泌抑制剂以及 免疫信号传导或抗病毒因子的细胞内抑制剂。我们项目的长期目标 是要揭示痘病毒免疫进化的机制，这将揭示基本 有关病毒宿主相互作用的原则，并为疫苗的开发提供知识 和抗病毒药。我们上一个融资期的重点是一个分泌的痘病毒interleukin-18 （IL-18）结合蛋白（IL-18bp），可防止IL-18诱导的IFN-€产生。我们 已经非常有生产力，并完成了所有具体目标。此外，我们发现了 I型干扰素（IFN），K1和C71,2的疫苗病毒（VAVV）两个细胞内抑制剂。这是 一个令人兴奋的发现，因为K1和C7是鼠尾病复制至关重要的宿主范围因素 在哺乳动物的宿主中，他们的行动机制长期以来一直是个谜。我们假设 K1和C7由于抑制了批判性，对于痘病毒复制至关重要 IFN诱导的抗病毒途径。因此揭示了K1和C7的作用机理 不仅会揭示痘病毒宿主托的分子基础，而且还会揭示关键的先天免疫 防御机制针对痘病毒。在下一个资金周期中，我们建议跟进我们的 在K1和C7上的发现并追求以下目标。 AIM 1。基于C7家族晶体结构的VAVV C7的结构功能分析 蛋白质。 目标2。确定K1和C7靶向的宿主抗病毒因子。 目标3。确定体内角色K1和C7的复制能力扮演 VAVV的免疫原性。