Pathogenesis of and host response to chikungunya virus infection of the central nervous system

中枢神经系统基孔肯雅病毒感染的发病机制和宿主反应

• 批准号: 9976617
• 负责人: VICTORIA K BAXTER
• 金额: $ 12.62万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976617
• 关键词: Acute Disease; Adaptive Immune System; Advisory Committees; Affect; Age; Alphavirus; Alphavirus Infections; Americas; Animal Model; Arboviruses; Arthritis; Arthritogenic; Autopsy; Award; B-Lymphocytes; C57BL/6 Mouse; Caribbean region; Central Nervous System Infections; Cessation of life; Chikungunya virus; Child; Clinical; Culicidae; Data; Development; Disease; Disease Outcome; Doctor of Philosophy; Emotional; Encephalitis; Encephalomyelitis; Exanthema; Flavivirus; Foundations; Funding; Future; Genetic; Genetic Variation; Geography; Human; Immune; Immune response; Immune system; Immunology; Individual; Infant; Infection; Inflammatory Response; Knowledge; Left; Maus Elberfeld virus; Mediating; Medicine; Meningitis; Mentors; Mentorship; Modeling; Mouse Strains; Mus; Myositis; Nervous System Trauma; Neuraxis; Neurologic; Neurologic Deficit; Neurological Models; Neurons; Neuropathogenesis; North Carolina; Outcome; Pathogenesis; Pathology; Pathway interactions; Patients; Peripheral; Phylogenetic Analysis; Play; Population; Predisposition; Public Health; Research; Research Personnel; Research Training; Role; Seizures; Severities; Severity of illness; Sindbis Virus; Solid; Supportive care; Systemic disease; T-Lymphocyte; Testing; Therapeutic; Time; Tissue Sample; Training; Translational Research; Universities; Vaccines; Variant; Veterinarians; Viral; Viral Pathogenesis; Virus; Virus Diseases; Virus Replication; base; career; chikungunya infection; collaborative environment; comparative; disability; doctoral student; experience; genetic strain; human disease; infectious disease model; mouse genetics; mouse model; nervous system disorder; neuropathology; neurovirulence; novel; professor; programs; skills; targeted treatment; virus genetics

Abstract The purpose of this K01 SERCA application is to provide the protected research time and mentorship necessary for Dr. Victoria Baxter, DVM, PhD, DACLAM to make the transition to independent investigator. Dr. Baxter is a veterinarian with a strong background in comparative medicine, viral immunology, and animal models of infectious disease, making her uniquely qualified for a career in translational research. Under the guidance of her mentor Dr. Mark Heise and an experienced interdisciplinary advisory committee, the training and aims outlined in this proposal will allow Dr. Baxter to expand her knowledge in viral and host genetics in order to establish a solid foundation for her own independent research program focused on understanding the pathogenesis of emerging and re-emerging viral diseases. The University of North Carolina at Chapel Hill will provide the interactive and collaborative environment necessary to support her transition to independence. Encephalitic arboviruses represent a re-emerging cause of human disease and disability, as patients who survive the initial acute disease are often left with lifelong neurological deficits. While chikungunya virus (CHIKV), an alphavirus that has recently spread to the Americas and Caribbean, typically causes a systemic disease characterized by rash and arthritis, individuals frequently develop neurological complications. Very little has been done to examine CHIKV encephalomyelitis, as no reliable small animal model currently exists. Most of the knowledge regarding the pathogenesis of alphavirus infection of the central nervous system (CNS) comes from the well-characterized mouse model of alphavirus encephalomyelitis using Sindbis virus. Outcome of CNS infection by Sindbis virus is dependent on both viral and mouse strain genetics, and CNS damage is primarily mediated by the immune response. This suggests three independent but interrelated factors drive CHIKV encephalomyelitis: viral genetics, host genetics, and the host immune system. The central hypothesis of the proposed studies is that CHIKV encephalomyelitis develops due to a combination of viral and host genetic factors, resulting in CNS damage that is primarily mediated by the host immune response rather than directly by CHIKV. This hypothesis will be tested with the following specific aims: Specific Aim #1: Determine if CHIKV genetic variation confers neurovirulence in a mouse model of CHIKV encephalomyelitis. Specific Aim #2: Elucidate the contribution of the adaptive immune system to CHIKV encephalomyelitis. Specific Aim #3: Determine if host genetic variation impacts susceptibility to CHIKV encephalomyelitis. These studies will generate valuable data that will provide a foundation for a future R01 application aimed at further elucidating mechanisms of CHIKV neuropathogenesis, and SERCA funding will provide Dr. Baxter with the skills necessary to establish similar models for examining other emerging viral diseases in the future.

抽象的 此K01 SERCA应用的目的是提供受保护的研究时间和指导 对于Victoria Baxter博士，DVM，博士和DACLAM的必要条件，才能过渡到独立研究者。博士 巴克斯特（Baxter）是一名兽医，在比较医学，病毒免疫学和动物方面具有强大的背景 传染病的模型，使她独特地有资格从事转化研究的职业。在 她的导师马克·海斯（Mark Heise）博士和经验丰富的跨学科咨询委员会的指导，培训 并在此提案中概述的目标将使巴克斯特博士能够扩大她对病毒的知识和宿主遗传学的知识 为了为自己的独立研究计划建立坚实的基础，旨在理解 出现和重新出现病毒疾病的发病机理。北卡罗来纳大学教堂山将 提供支持她向独立过渡所必需的互动和协作环境。 脑病病毒代表了人类疾病和残疾的重新出现，因为患者 最初的急性疾病的生存通常会留下终生的神经系统缺陷。而chikungunya病毒 （Chikv），最近传播到美洲和加勒比海的α病毒通常会引起全身性 以皮疹和关节炎为特征的疾病，个体经常出现神经系统并发症。非常 由于目前不存在可靠的小动物模型，因此几乎没有做任何事情来检查CHIKV脑脊髓炎。 有关中枢神经系统（CNS）α病毒感染发病机理的大多数知识 来自使用信德氏病毒的α病毒脑脊髓炎的特征良好的小鼠模型。结果 Sindbis病毒感染中枢神经系统的感染取决于病毒和小鼠菌株遗传学，CNS损伤是 主要由免疫反应介导。这表明三个独立但相互关联的因素驱动 CHIKV脑脊髓炎：病毒遗传学，宿主遗传学和宿主免疫系统。中心假设 拟议的研究是，由于病毒和宿主的结合，CHIKV脑脊髓炎发展 遗传因素，导致CNS损伤，主要是由宿主免疫反应介导的，而不是 直接由Chikv。该假设将以以下特定目的进行检验： 特定目的＃1：确定CHIKV遗传变异是否同时赋予CHIKV小鼠模型中的神经动力学 脑脊髓炎。 特定目的＃2：阐明自适应免疫系统对CHIKV脑脊髓炎的贡献。 特定目的＃3：确定宿主遗传变异是否影响对CHIKV脑脊髓炎的敏感性。 这些研究将产生有价值的数据，为未来R01应用程序提供基础 进一步阐明CHIKV神经病生成和SERCA资金的机制将为Baxter博士提供 建立类似模型以检查其他新兴病毒疾病所需的技能。