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

• 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
• 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

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（Powassan virus，POWV）是一种新发现的蜱传神经侵入性黄病毒。类似于蚊子传播的 黄病毒如西尼罗河病毒和日本脑炎病毒，POWV引起神经侵入性疾病， 包括脑炎脑膜炎瘫痪和死亡虽然大多数黄病毒感染导致 无症状感染，症状性黄病毒感染的一个子集进展为神经侵入性疾病， 虽然影响严重疾病易感性的因素尚未完全了解， POWV的致病机制。我们假设宿主抗病毒反应基因的变异 导致黄病毒感染后不同的疾病结果。我们建议使用协作交叉 (CC)小鼠来表征POWV发病机制的特征并鉴定导致POWV的宿主基因 易感性CC是重组近交系小鼠的小鼠遗传参考群体，通过 将代表三个野生衍生的和五个经典实验室小鼠品系的八个创始品系进行杂交。的CC 以可重复的方式捕获实验室小鼠的遗传多样性，因为约80个品系中的每一个都具有 已知的和固定的基因组，为绘制复杂性状提供了一个有价值的工具。在初步研究中，我们感染了 一组携带POWV的Oas1b基因缺失CC小鼠品系，观察到一系列易感性表型，表明 除了已充分表征的黄病毒限制因子Oas1b外，还有宿主因子调节POWV 小鼠的发病机制。我们鉴定了多个高感品系（100%致死率），包括CC 071和一个高感品系（100%致死率）。 单一抗性系（0%致死率），CC 045。基于这些初步数据，我们建议i）确定病毒和 在敏感和抗性CC系中POWV发病机理免疫学特征，和ii）定量作图 利用感病系和抗病系的F2代，研究了与POWV致病相关的性状基因座（QTL）。在 目的1，我们将评估POWV感染后CNS中的病毒载量和浸润性白细胞， POWV在原代细胞中的复制，并使用敏感（CC071）和 抗性（CC 045）CC系。在目标2中，我们将评估POWV致死率、病毒载量和浸润性白细胞， F2小鼠CNS和与这些表型相关的QTL作图，以鉴定 有助于POWV易感性。这些研究将进一步加深我们对黄病毒神经侵袭性的理解。 通过鉴定调节小鼠对POWV易感性的宿主遗传因子， 深入了解更广泛地影响神经侵袭性黄病毒的因素。拟议的培训计划将侧重于 建立定量遗传学技术的基础，以研究病毒和免疫机制， POWV发病机制，并将准备我的职业生涯作为一个独立的研究人员使用定量遗传学 研究传染病的技术。