Host genetic determinants of neuroinvasive flavivirus pathogenesis

神经侵袭性黄病毒发病机制的宿主遗传决定因素

基本信息

批准号：
10576806
负责人：
BRITTANY JASPERSE
金额：
$ 1.91万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2023-05-19
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10576806
关键词：
Address Antiviral Response Blood - brain barrier anatomy Bypass Cells Central Nervous System Cessation of life Characteristics Communicable Diseases Complex Data Dendritic Cells Dengue Virus Disease Disease Outbreaks Disease Outcome Encephalitis Exhibits Fever Flavivirus Flavivirus Infections Foundations Future Genes Genetic Genetic Determinism Genetic Techniques Genetic Variation Genome Growth Iceberg Immune Immunologic Factors Immunologics Inbred Mouse Incidence Individual Infection Inflammatory Integration Host Factors Investigation Ixodes Japanese encephalitis virus Laboratory mice Leucocytic infiltrate Ligase Lyme Disease Macrophage Maps Meningitis Mus Neurons North America Outcome Paralysed Pathogenesis Pathogenicity Pathology Phenotype Population Powassan virus Predisposition Quantitative Genetics Quantitative Trait Loci Recombinants Reproducibility Research Personnel Resistance Stimulus Symptoms Testing Tick-Borne Diseases Training United States Variant Viral Viral Load result Viral Pathogenesis Viremia Virus Virus Diseases Virus Replication West Nile virus Work Zika Virus blood-brain barrier permeabilization candidate identification career causal variant genetic element insight mosquito-borne mouse genetics neurovirulence novel oligoadenylate response subcutaneous tick transmission tick-borne tick-borne flavivirus tool trait transmission process viral resistance virus identification

项目摘要

PROJECT SUMMARY Powassan virus (POWV) is an emerging tick-borne neuroinvasive flavivirus. Similar to mosquito-borne flaviviruses such as West Nile virus and Japanese encephalitis virus, POWV causes neuroinvasive disease, including encephalitis, meningitis, paralysis, and death. While the majority of flavivirus infections result in asymptomatic infection, a subset of symptomatic flavivirus infections progress to neuroinvasive disease, although the factors influencing susceptibility to severe disease are not fully understood and little is known about the pathogenic mechanisms of POWV. We hypothesize that variation in host antiviral response genes contributes to differential disease outcome following flavivirus infection. We propose to use Collaborative Cross (CC) mice to characterize features of POWV pathogenesis and identify host genes that contribute to POWV susceptibility. The CC is a mouse genetic reference population of recombinant inbred mice generated by crossing eight founder lines that represent three wild-derived and five classical laboratory mouse lines. The CC captures the genetic diversity of laboratory mice in a reproducible manner, since each of the ~80 lines has a known and fixed genome, providing a valuable tool for mapping complex traits. In preliminary studies, we infected a panel of Oas1b-null CC mouse lines with POWV and observed a range of susceptibility phenotypes, suggesting there are host factors other than the well-characterized flavivirus restriction factor Oas1b that modulate POWV pathogenesis in mice. We identified multiple highly susceptible lines (100% lethality), including CC071, and a single resistant line (0% lethality), CC045. Building on this preliminary data, we propose to i) determine viral and immunologic features of POWV pathogenesis in susceptible and resistant CC lines, and ii) map Quantitative Trait Loci (QTL) associated with POWV pathogenesis using F2 progeny of susceptible and resistant lines. In Aim 1, we will evaluate viral loads and infiltrating leukocytes in the CNS following POWV infection, characterize POWV replication in primary cells, and assess blood-brain barrier permeability, using susceptible (CC071) and resistant (CC045) CC lines. In Aim 2, we will evaluate POWV lethality, viral loads, and infiltrating leukocytes in the CNS of F2 mice and map QTL associated with these phenotypes to identify host genetic elements that contribute to POWV susceptibility. The proposed studies will further our understanding of flavivirus neuroinvasive disease through identification of host genetic factors that modulate POWV susceptibility in mice and provide insights into factors that impact neuroinvasive flaviviruses more broadly. The proposed training plan will focus on building a foundation in quantitative genetics techniques to investigate viral and immunologic mechanisms of POWV pathogenesis, and will prepare me for a career as an independent investigator using quantitative genetics techniques to study infectious diseases.

项目摘要 Powassan病毒（POWV）是一种新兴的tick传播神经侵袭性黄素病毒。类似于蚊子出生西尼罗河病毒和日本脑炎病毒等黄素病毒会引起神经侵袭性疾病，包括脑炎，脑膜炎，瘫痪和死亡。大多数黄病毒感染导致无症状感染，一部分有症状的黄病毒感染发展为神经侵染疾病，尽管影响严重疾病易感性的因素尚不完全了解，并且对 POWV的致病机制。我们假设宿主抗病毒反应基因的变化黄病毒感染后有助于差异疾病结果。我们建议使用协作十字架（CC）小鼠表征POWV发病机理的特征并识别有助于POWV的宿主基因敏感性。 CC是小鼠遗传参考群，是由越过八个代表三个野生衍生和五个经典实验室小鼠系的创始人线。 CC 以可重复的方式捕获实验室小鼠的遗传多样性，因为〜80行中的每条线都有已知和固定的基因组，为映射复杂性状提供了有价值的工具。在初步研究中，我们感染了一组具有POWV的OAS1B-NULL CC小鼠线，观察到一系列易感性表型，表明除特征良好的黄病毒限制因子OAS1B外，还有其他其他因素小鼠发病机理。我们确定了多个高度易感线（100％致死性），包括CC071和A 单抗性线（0％致死性），CC045。在此初步数据的基础上，我们建议i）确定病毒和 POWV发病机理的免疫学特征在易感和抗性CC系中，ii）映射定量使用易感和抗性线的F2后代与POWV发病机理相关的特质基因座（QTL）。在 AIM 1，我们将评估POWV感染后CNS中CNS中的病毒载荷和浸润的白细胞使用易感性（CC071）和抗性（CC045）CC线。在AIM 2中，我们将评估POWV致死性，病毒载荷和浸润性白细胞 F2小鼠的中枢神经系统和与这些表型相关的MAP QTL，以识别宿主遗传元素有助于POWV敏感性。拟议的研究将进一步了解我们对Flavivivirus神经活动的理解通过鉴定调节小鼠POWV易感性并提供的宿主遗传因素的疾病深入了解影响神经侵袭性黄素病毒的因素。拟议的培训计划将重点建立定量遗传学技术的基础，以研究 POWV发病机理，将为我准备使用定量遗传学的独立研究者的职业研究传染病的技术。