Defining the impact of complement inhibition by tick saliva in tick-borne virus evolution and adaptive immune responses in murine models of infection

由壁虱传播的病毒(Tbv)引起的疾病在过去十年中发病率一直在增加，很少见。 经批准的疫苗或疗法。其中，壁虱传播的黄病毒鲍瓦桑病毒(POWV)是一种RNA 一种病毒，经常引起人类的神经侵袭性疾病，由硬蜱传播。这些和其他 扁虱体内有一种独特的唾液蛋白质，可以产生免疫抑制的环境。 在血餐期间能够长期依附于宿主。宿主-TBV相互作用的一个方面是不好的 人们所了解的是，在这个利基环境中复制的病毒病原体可能会获得优势。这口唾液 已知激活传播(SAT)与POWV感染有关，但其背后的潜在机制 仍有待阐明。在本申请中提出的这项研究将剖析SGE的一个重要方面 免疫抑制-补体抑制-影响获得性免疫反应的发展 接种和未接种疫苗的小鼠宿主，以及病毒复制和随后的传播如何 复制的次要位置可能会导致TBV疾病。 除了在TBV和新发传染病方面的现有专业知识外，我们的团队还具有 POWV感染小鼠模型中病毒复制动力学及特异性B、T细胞反应的研究 感染。此外，我们与我们的合作者合作，开发了一种基于病毒样颗粒(VLP)的 能够预防致命的POWV挑战的疫苗接种策略。补体抑制如何影响 在接种和未接种POWV的小鼠宿主中，POWV特异性B和T细胞反应的发展是 目标1的主题。目标2侧重于量化补体抑制对神经病理疾病的影响 以及病毒进化来驱动小鼠宿主中的疾病。 本建议中描述的研究金培训计划旨在解决申请人在以下方面的重要差距 在完成博士论文答辩之前接受了培训。这些差距将主要通过以下方式解决：1) 推进申请者病毒学和免疫学工具以及影响较大的出版物的资料库，2)允许 申请人获得分析下一代测序数据的新技能，3)鼓励申请人的 参加面对面的会议，目的是建立联系并寻求合适的博士后导师。这个 本建议书中提出的研究和培训目标将在发起人和 在圣路易斯大学和科罗拉多州立大学共同赞助的高度协作和以实习生为重点的 布景。

Disease caused by tick-borne viruses (TBVs) has been increasing in incidence in the past decade, with few approved vaccines or therapeutics. Among these, the tick-borne flavivirus Powassan virus (POWV) is an RNA virus which frequently causes neuroinvasive disease in humans and transmitted by Ixodes ticks. These and other ticks are equipped with a unique store of salivary proteins that create an immunosuppressive environment enabling long-term attachment to a host during a bloodmeal. One aspect of host-TBV interactions that is not well understood is how the viral pathogens replicating in this niche may be afforded an advantage. This saliva activated transmission (SAT) is known to occur with POWV infection, but the underlying mechanisms behind it remain to be elucidated. This research proposed in this application will dissect how one important aspect of SGE immunosuppression—complement inhibition—impacts the development of the adaptive immune response in vaccinated and unvaccinated murine hosts, and how virus replication and subsequent dissemination to secondary sites of replication can drive TBV disease. In addition to existing expertise in TBVs and emerging infectious disease, our group has characterized the kinetics of viral replication and the development of POWV-specific B and T cell responses in murine models of infection. Furthermore, in conjunction with our collaborators, we have developed a virus-like particle (VLP) based vaccination strategy capable of protecting against lethal POWV challenge. How complement inhibition impacts the development of POWV-specific B and T cell responses in vaccinated and unvaccinated murine hosts is the subject of Aim 1. Aim 2 focuses on quantifying the impact of complement inhibition on neuropathological disease and virus evolution to drive disease in the murine host. The fellowship training plan described in this proposal is designed to address important gaps in the applicant’s training prior to completion of her doctoral dissertation defense. These gaps will primarily be addressed by: 1) advancing the applicants repertoire of virology and immunology tools and high-impact publications, 2) allowing the applicant to acquire a new skillset analyzing next generation sequencing data, 3) encouraging the applicant’s attendance at in-person meetings for purposes of networking and seeking a suitable postdoctoral mentor. The research and training goals set forth in this proposal will be accomplished in the environment of the sponsor and co-sponsors at Saint Louis University and Colorado State University in a highly collaborative and trainee focused setting.