Poxvirus Immune Evasion Mechanisms

痘病毒免疫逃避机制

基本信息

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
项目类别：
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

项目摘要

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出现或重新出现的病原体以及一些有前途的传染病和癌症疫苗载体它们是独一无二的。病毒，因为它们编码大量专门用于逃避宿主的蛋白质这些蛋白质包括细胞因子的分泌抑制剂以及免疫反应。免疫信号或抗病毒因子的细胞内抑制剂我们项目的长期目标。揭示痘病毒免疫逃避的机制，这将揭示根本性的有关病毒与宿主相互作用的原理，并为疫苗的开发提供知识我们上一个资助期的重点是分泌性痘病毒白细胞介素 18。 (IL-18) 结合蛋白 (IL-18BP)，可防止 IL-18 诱导 IFN-¿生产.我们非常富有成效并实现了所有具体目标此外，我们发现。痘苗病毒 (VACV) I 型干扰素 (IFN) 的两种细胞内抑制剂，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在哺乳动物宿主中，但其作用机制长期以来一直是个谜。 K1 和 C7 对于痘病毒复制至关重要，因为它们抑制了关键的 IFN诱导的抗病毒途径因此揭示了K1和C7的作用机制。不仅将揭示痘病毒宿主向性的分子基础，而且还将揭示关键的先天免疫在下一个资助周期中，我们建议跟进我们的痘病毒防御机制。 K1 和 C7 的发现并追求以下目标。目标1.基于C7族晶体结构的VACV C7的结构-功能分析蛋白质。目标 2. 确定 K1 和 C7 所针对的宿主抗病毒因子。目标 3. 确定 K1 和 C7 在复制能力和复制能力方面发挥的体内作用 VACV 的免疫原性。