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
基本信息
- 批准号:10535945
- 负责人:
- 金额:$ 1.35万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAntibody ResponseAntiviral AgentsAreaB-LymphocytesBlack-legged TickCD8-Positive T-LymphocytesCell CompartmentationColoradoComplementComplement ActivationComplement InactivatorsComplement Membrane Attack ComplexComplement ReceptorCytolysisDataDevelopmentDiseaseDisease OutcomeEmerging Communicable DiseasesEnvironmentEvolutionFellowshipFlavivirusFlavivirus InfectionsFutureGoalsHumanImmuneImmune responseImmunologyImmunosuppressionImpairmentIncidenceInfectionInflammationInnate Immune SystemIxodesIxodidaeKineticsLeadMediatingMentorsModelingMorbidity - disease rateMusNeuraxisOutcomePathogenesisPathologicPersonsPopulationPowassan virusProductionProtein FamilyPublicationsRNA VirusesReagentRecombinantsResearchResearch TrainingRoleSaintsSalivaSalivary GlandsSalivary ProteinsSecondary toSiteSkinStructure of germinal center of lymph nodeT cell responseT-LymphocyteT-Lymphocyte EpitopesTherapeuticTick-Borne DiseasesTicksTissuesTrainingUniversitiesVaccinatedVaccinationVaccinesValidationViralVirusVirus DiseasesVirus ReplicationVirus-like particleadaptive immune responseadaptive immunitybasecell injurycell killingcostdesignfitnesshistopathological examinationimprovedmeetingsmortalitymouse modelneuropathologynext generation sequencingnovelpathogenpathogenic viruspressureresponsesaliva mediatedtherapeutic targettick bitetick salivatick transmissiontick-bornetick-borne flavivirustick-borne virustooltransmission processunvaccinatedvaccination strategyviral transmissionvirology
项目摘要
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.
在过去的十年里,蜱传病毒(TBV)引起的疾病的发病率一直在增加,
批准的疫苗或治疗剂。其中,蜱传黄病毒属Powassan病毒(POWV)是一种RNA病毒,
一种经常引起人类神经侵入性疾病并由硬蜱传播的病毒。这些和其他
蜱拥有一种独特的唾液蛋白库,可以创造一个免疫抑制环境
在吸血过程中能够长期附着在宿主身上宿主-TBV相互作用的一个方面,
了解病毒病原体如何在这个小生境中复制可以获得优势。这些唾液
已知POWV感染时会发生活化传播(SAT),但其背后的机制尚不清楚。
仍有待阐明。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-影响适应性免疫反应的发展,
接种疫苗和未接种疫苗的鼠宿主,以及病毒如何复制和随后传播到
二级复制位点可以导致TBV疾病。
除了现有的TBV和新兴传染病的专业知识,我们的团队已经确定了
病毒复制的动力学和在小鼠模型中的POWV特异性B和T细胞应答的发展
感染此外,与我们的合作者一起,我们开发了一种基于病毒样颗粒(VLP)的
疫苗接种策略能够保护免受致命的POWV攻击。补体抑制如何影响
在接种和未接种的鼠宿主中发生的POWV特异性B和T细胞应答是
目标1的主题。目标2着重于量化补体抑制对神经病理学疾病的影响
和病毒进化来驱动鼠类宿主的疾病。
本建议书所述的研究金培训计划旨在弥补申请人在
在完成博士论文答辩之前接受培训。这些差距将主要通过以下方式解决:1)
推进申请人的病毒学和免疫学工具库和高影响力出版物,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
参加面对面的会议,以建立网络和寻找合适的博士后导师。的
本提案中提出的研究和培训目标将在申办者的环境中完成,
共同赞助商在圣刘易斯大学和科罗拉多州立大学在一个高度协作和培训重点
设置.
项目成果
期刊论文数量(0)
专著数量(0)
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