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

定义蜱唾液抑制补体对蜱传病毒进化和小鼠感染模型适应性免疫反应的影响

• 批准号: 10535945
• 负责人: Emily Taylor Stone
• 金额: $ 1.35万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2023-04-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10535945
• 关键词: Address; Antibody Response; Antiviral Agents; Area; B-Lymphocytes; Black-legged Tick; CD8-Positive T-Lymphocytes; Cell Compartmentation; Colorado; Complement; Complement Activation; Complement Inactivators; Complement Membrane Attack Complex; Complement Receptor; Cytolysis; Data; Development; Disease; Disease Outcome; Emerging Communicable Diseases; Environment; Evolution; Fellowship; Flavivirus; Flavivirus Infections; Future; Goals; Human; Immune; Immune response; Immunology; Immunosuppression; Impairment; Incidence; Infection; Inflammation; Innate Immune System; Ixodes; Ixodidae; Kinetics; Lead; Mediating; Mentors; Modeling; Morbidity - disease rate; Mus; Neuraxis; Outcome; Pathogenesis; Pathologic; Persons; Population; Powassan virus; Production; Protein Family; Publications; RNA Viruses; Reagent; Recombinants; Research; Research Training; Role; Saints; Saliva; Salivary Glands; Salivary Proteins; Secondary to; Site; Skin; Structure of germinal center of lymph node; T cell response; T-Lymphocyte; T-Lymphocyte Epitopes; Therapeutic; Tick-Borne Diseases; Ticks; Tissues; Training; Universities; Vaccinated; Vaccination; Vaccines; Validation; Viral; Virus; Virus Diseases; Virus Replication; Virus-like particle; adaptive immune response; adaptive immunity; base; cell injury; cell killing; cost; design; fitness; histopathological examination; improved; meetings; mortality; mouse model; neuropathology; next generation sequencing; novel; pathogen; pathogenic virus; pressure; response; saliva mediated; therapeutic target; tick bite; tick saliva; tick transmission; tick-borne; tick-borne flavivirus; tick-borne virus; tool; transmission process; unvaccinated; vaccination strategy; viral transmission; virology

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.

在过去的十年中，由tick传播病毒引起的疾病（TBV）的发生率一直在增加，很少 批准的疫苗或治疗。其中，tick传播黄病毒Powassan病毒（POWV）是RNA 经常在人类中引起神经侵袭性疾病并由ixodes tick传播的病毒。这些和其他 壁虱配备了独特的唾液蛋白商店，可创造一种免疫抑制环境 在血液中使宿主长期依恋。主机-TBV交互的一个方面不好 理解是如何在该利基中复制的病毒病原体具有优势。这个唾液 已知活化传播（SAT）发生在POWV感染中，但其背后的基本机制 仍然有待阐明。本应用程序中提出的这项研究将剖析SGE的一个重要方面 免疫抑制 - 结合抑制 - 影响适应性免疫反应的发展 接种疫苗和未接种的鼠宿主，以及病毒复制和随后如何传播到 复制的次要部位可以驱动TBV疾病。 除了在TBV和新兴的传染病方面的现有专业知识外，我们的小组还表征了 病毒复制的动力学以及在鼠模型中的POWV特异性B和T细胞反应的发展 感染。此外，与我们的合作者一起，我们开发了基于病毒的粒子（VLP） 疫苗接种策略能够防止致命POWV挑战。完成抑制如何影响 在接种和未接种的鼠宿主中，POWV特异性B和T细胞反应的发展是 目标1。AIM2的重点是量化完成抑制对神经病理学疾病的影响 和病毒进化以驱动鼠宿主中的疾病。 本提案中描述的奖学金培训计划旨在解决申请人的重要差距 在完成博士学位论文辩护之前进行培训。这些差距将通过：1）解决。 推进申请人的病毒学和免疫学工具和高影响力出版物的曲目，2）允许 申请人获得新的技能分析下一代测序数据的新技能，3）鼓励申请人的 出席面对面会议，以进行网络和寻求合适的博士后心理。 该提案中规定的研究和培训目标将在赞助商的环境中实现 圣路易斯大学和科罗拉多州立大学的共同发起人，以高度合作和受训者为重点 环境。