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

摘要 此K01 SERCA应用程序的目的是提供受保护的研究时间和指导 维多利亚巴克斯特博士，DVM，PhD，DACLAM过渡为独立研究者。博士 巴克斯特是一名兽医，在比较医学、病毒免疫学和动物免疫学方面具有很强的背景。 传染病模型，使她成为唯一有资格从事转化研究的人。下 她的导师马克海瑟博士和经验丰富的跨学科咨询委员会的指导下，培训 本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， 为了建立一个坚实的基础，她自己的独立研究计划，重点是了解 新出现和重新出现的病毒性疾病的发病机制。位于查佩尔山的北卡罗来纳州大学将 提供必要的互动和协作环境，以支持她向独立过渡。 脑炎虫媒病毒代表了人类疾病和残疾的重新出现的原因， 在最初的急性疾病中幸存下来的人往往会留下终身的神经缺陷。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 疾病的特点是皮疹和关节炎，个人经常发展神经系统并发症。非常 由于目前还没有可靠的小动物模型，所以对CHIKV脑脊髓炎的研究很少。 关于甲病毒感染中枢神经系统（CNS）的发病机制的大部分知识 来自使用辛德毕斯病毒的甲病毒脑脊髓炎的充分表征的小鼠模型。结果 辛德毕斯病毒感染中枢神经系统的风险依赖于病毒和小鼠品系的遗传学， 主要由免疫反应介导。这表明有三个独立但相互关联的因素驱动着 CHIKV脑脊髓炎：病毒遗传学，宿主遗传学和宿主免疫系统。核心假设 CHIKV脑脊髓炎的发展是由于病毒和宿主 遗传因素，导致中枢神经系统损伤，主要由宿主免疫反应介导，而不是 直接通过CHIKV。将以下列具体目标检验这一假设： 具体目标#1：确定CHIKV遗传变异是否在CHIKV小鼠模型中赋予神经毒力 脑脊髓炎 具体目标#2：阐明适应性免疫系统对CHIKV脑脊髓炎的贡献。 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应用提供基础， 进一步阐明CHIKV神经发病机制和SERCA基金将为巴克斯特博士提供 建立类似模型的必要技能，用于将来检查其他新出现的病毒性疾病。

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.