Mechanisms of orthopoxvirus host control and viral immune evasion

描述（由申请方提供）：本提案重点关注正痘病毒（OPXV）感染的免疫控制，OPXV是一种医学相关的大型双链DNA病毒属，包括天花病毒（天花的病原体）。虽然天花已经从自然感染中根除，但人们仍然对它作为生物武器的使用表示严重关切。此外，人畜共患病感染是由相关的OPXV引起的，包括猴痘病毒和牛痘病毒（CPXV）。OPXV具有编码逃避宿主免疫应答的病毒蛋白的开放阅读框（ORF）。该应用以CPXV为中心，因为它被认为具有最大的免疫逃避基因库，并且在啮齿动物中流行，使得实验小鼠中的CPXV感染适于研究宿主-病原体相互作用。在已发表和未发表的研究中，申请人的原理证明数据表明，CPXV研究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，并且对这些分子的研究将揭示对控制病毒的宿主机制的新见解。为了解决这些假设，申请人召集了一个由四名高素质的主要研究人员组成的小组，他们在研究方面有着重要的记录。 OPXV和CPXV将合作开展三个不同的项目。因此，该U19申请的总体具体目的是：1）确定CPXV中阻碍宿主免疫应答的ORF，特别是由自然杀伤（NK）和T细胞介导的那些，并评估用特异性缺乏免疫逃避基因的病毒在小鼠中体内感染的结果。2)通过识别特定的宿主相互作用配体和受体，确定这些CPXV编码蛋白调节免疫应答的机制。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的免疫反应。因此，该提案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 In published and unpublished studies, the applicants have proof-of-principle data indicating that CPXV investigations can inform topics of general interest regarding immune control of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.