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，博士，DACLAM需要过渡到独立调查员。Dr。 巴克斯特是一名兽医，在比较医学、病毒免疫学和动物方面都有很强的背景 传染病模型，使她成为从事翻译研究事业的唯一合格人选。在.之下 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 这项提案中概述的目标将使巴克斯特博士能够扩大她在病毒和宿主遗传学方面的知识 以便为她自己的独立研究计划奠定坚实的基础，重点是了解 新出现和再次出现的病毒疾病的发病机制。北卡罗来纳大学教堂山分校将 提供必要的互动和协作环境，以支持她向独立的过渡。 脑炎虫媒病毒是导致人类疾病和残疾的又一种原因，因为患者 在最初的急性疾病中幸存下来的人往往会留下终生的神经缺陷。而基孔肯雅病毒 (CHIKV)是一种最近蔓延到美洲和加勒比的甲型病毒，通常会导致系统性 以皮疹和关节炎为特征的疾病，个人经常出现神经系统并发症。非常 对CHIKV脑脊髓炎的研究很少，因为目前还没有可靠的小动物模型存在。 大多数关于中枢神经系统甲型病毒感染发病机制的知识 来自使用辛德比斯病毒的甲型病毒性脑脊髓炎小鼠模型。结果 Sindbis病毒感染中枢神经系统的可能性取决于病毒和小鼠株系的遗传学，而中枢神经系统损伤是 主要由免疫反应调节。这表明有三个独立但又相互关联的因素推动 CHIKV脑脊髓炎：病毒遗传学、宿主遗传学和宿主免疫系统。中心假说 建议的研究之一是CHIKV脑脊髓炎是由于病毒和宿主的共同作用而发生的 遗传因素导致的中枢神经系统损伤主要由宿主免疫反应介导，而不是 直接由CHIKV提供。这一假设将以以下具体目标进行检验： 具体目标#1：确定CHIKV基因变异是否赋予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脑脊髓炎的贡献。 具体目标#3：确定宿主遗传变异是否影响CHIKV脑脊髓炎的易感性。 这些研究将产生有价值的数据，这些数据将为未来旨在 进一步阐明CHIKV神经发病机制，SERCA资助将为巴克斯特博士提供 为未来检查其他新出现的病毒疾病建立类似模型所需的技能。

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.