Mechanisms of orthopoxvirus host control and viral immune evasion

描述(申请人提供)：这项提案侧重于正痘病毒(OPXV)感染的免疫控制，正痘病毒是一种医学上相关的大型双链DNA病毒属，包括天花的病原体天花。尽管天花已经从自然感染中根除，但它作为生物武器的使用仍然存在重大担忧。此外，人畜共患感染是由相关的OPXV引起的，包括猴痘病毒和牛痘病毒(CPXV)。OPXV具有编码病毒蛋白的开放阅读框架(ORF)，可以逃避宿主的免疫反应。这种应用集中在CPXV上，因为它被认为拥有最大的免疫逃避基因库，并且在啮齿动物中流行，使CPXV在实验小鼠中的感染适合于研究宿主与病原体的相互作用。在已发表和未发表的研究中，申请者拥有原则证明数据，表明CPXV调查可以为有关病毒免疫控制的普遍感兴趣的主题提供信息。因此，总体假设是CPXV编码逃避宿主免疫的新分子，对这些分子的研究将揭示控制病毒的宿主机制的新见解。为了解决这些假设，申请者组织了一个由四名非常合格的首席调查人员组成的小组，他们在研究中有显著的记录 OPXV和CPXV在三个不同的项目上合作。因此，U19应用的总体特定目标是：1)确定CPXV中阻碍宿主免疫反应的ORF，特别是那些由自然杀伤(NK)和T细胞介导的ORF，并评估缺乏免疫逃避基因的病毒体内感染的结果。2)通过识别特定的宿主相互作用的配体和受体，确定这些CPXV编码的蛋白调节免疫反应的机制。3)确定CPXV免疫逃避蛋白与宿主靶标相互作用的结构基础。4)确定CPXV是否调节人体免疫反应。5)确定其他宿主对CPXV的免疫应答。因此，这项建议有可能导致具有临床意义的进展。

DESCRIPTION (provided by applicant): This proposal is focused on immune control of infections due to orthopoxviruses (OPXVs), a medically relevant genus of large double-stranded DNA viruses that includes variola, the causative agent of smallpox. Although smallpox has been eradicated from natural infections, there is still major concern about its use as a bioweapon. Moreover, zoonotic infections are caused by related OPXVs, including monkeypox virus, and cowpox virus (CPXV). The OPXVs possess open reading frames (ORFs) encoding viral proteins that evade the host immune response. This application centers on CPXV because it is thought to have the largest repertoire of immune evasion genes and is endemic in rodents making CPXV infections in experimental mice appropriate for study of host-pathogen interactions. In published and unpublished studies, the applicants have proof-of-principle data indicating that CPXV investigations can inform topics of general interest regarding immune control of viruses. Therefore, the overall hypotheses are that CPXV encodes novel molecules that evade host immunity and that study of these molecules will reveal novel insights into host mechanisms controlling viruses. To address these hypotheses, the applicants have assembled a group of four highly qualified principal investigators with significant track records in studying OPXVs and CPXV to work on three distinct projects in collaboration. Thus, the overall Specific Aims of this U19 application are: 1) Determine the ORFs in CPXV that thwart the host immune response, particularly those mediated by natural killer (NK) and T cells and assess the outcome of in vivo infections in mice with viruses specifically lacking the immune evasion genes. 2) Determine the mechanism by which these CPXV encoded proteins modulate the immune response by identifying the specific host interacting ligands and receptors. 3) Determine the structural basis for the interaction of CPXV immune evasion proteins with host targets. 4) Determine if CPXV modulates the human immune response. 5) Determine other host immune responses to CPXV. Therefore, this proposal has the potential to lead to advances with clinical significance.