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

基本信息

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
项目类别：
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

项目摘要

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 申请的目的是提供受保护的研究时间和指导 Victoria Baxter 博士（DVM、PhD、DACLAM）过渡为独立研究者所必需的。博士。 Baxter 是一位兽医，在比较医学、病毒免疫学和动物学方面拥有深厚的背景传染病模型，使她具有从事转化研究职业的独特资格。下在她的导师 Mark Heise 博士和经验丰富的跨学科咨询委员会的指导下，培训该提案中概述的目标将使巴克斯特博士能够扩展她在病毒和宿主遗传学方面的知识为了为她自己的独立研究计划奠定坚实的基础，重点是了解新出现和重新出现的病毒性疾病的发病机制。北卡罗来纳大学教堂山分校将提供支持她向独立过渡所需的互动和协作环境。脑炎虫媒病毒是人类疾病和残疾的重新出现的原因，因为患者在最初的急性疾病中幸存下来的人通常会留下终生的神经功能缺陷。虽然基孔肯雅病毒（CHIKV）是一种最近传播到美洲和加勒比地区的甲病毒，通常会引起系统性感染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，因此在检查 CHIKV 脑脊髓炎方面做得很少。大多数关于中枢神经系统（CNS）甲病毒感染发病机制的知识来自使用辛德比斯病毒的甲病毒脑脊髓炎小鼠模型。结果辛德比斯病毒感染中枢神经系统的程度取决于病毒和小鼠品系的遗传学，中枢神经系统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。中心假设拟议研究的其中一个内容是，CHIKV 脑脊髓炎是由于病毒和宿主的共同作用而发生的遗传因素，导致中枢神经系统损伤，主要是由宿主免疫反应介导的，而不是直接由 CHIKV 提供。该假设将通过以下具体目标进行检验：具体目标 #1：确定 CHIKV 遗传变异是否赋予 CHIKV 小鼠模型神经毒力脑脊髓炎。具体目标#2：阐明适应性免疫系统对 CHIKV 脑脊髓炎的影响。具体目标#3：确定宿主遗传变异是否影响对 CHIKV 脑脊髓炎的易感性。这些研究将产生有价值的数据，为未来的 R01 应用奠定基础进一步阐明 CHIKV 神经发病机制，SERCA 资助将为 Baxter 博士提供建立类似模型以检查未来其他新出现的病毒性疾病所需的技能。