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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：
10387019
负责人：
BRITTANY JASPERSE
金额：
$ 6.76万
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 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10387019
关键词：
Address Antiviral Response Blood - brain barrier anatomy Bypass Cells 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 Leukocytes Ligase Maps Meningitis Mus Neuraxis 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 career causal variant genetic element insight macrophage mosquito-borne mouse genetics neurovirulence novel oligoadenylate response subcutaneous tick transmission tick-borne tick-borne flavivirus tool trait viral resistance

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.

项目总结