Mechanisms of Neuropathogenic Rift Valley Fever in a Novel Rat Model

 描述（由申请方提供）：了解虫媒病毒引起的神经系统疾病的发病机制是使用药物或疫苗治疗致死性病毒性脑炎的基础。裂谷热是一种全球重要的新兴人畜共患虫媒病毒病，对人类和牲畜社区构成重大风险。人的RVFV感染可导致一系列临床结果，包括急性发热性疾病， 严重肝病或迟发性脑炎。不同的人类临床结果背后的机制尚不明确，代表了我们对这种新兴病毒性疾病的理解中的空白。长期目标是了解RVFV感染后导致一系列临床结果的病理生理机制，以及对预防RVF至关重要的免疫反应。本提案的总体目标是确定裂谷热病毒如何发生神经侵袭，以及宿主免疫反应在神经系统疾病和感染结果中的作用。该提议的中心假设是，在RVFV感染的大鼠中，脑中嗜中性粒细胞介导的宿主炎症反应加剧了神经侵袭和神经系统疾病。中心假设将通过以下具体目的来解决：1）确定RVFV的神经侵袭途径。由于关于RVFV如何侵入中枢神经系统的知识存在很大差距，因此将确定从感染部位到大脑的神经侵入途径。2)确定中性粒细胞浸润到大脑中如何影响神经系统疾病。初步数据表明，中性粒细胞的募集有助于免疫介导的组织损伤在感染大鼠的大脑。为了检验这一假设，将测量RVFV感染后中性粒细胞向脑内的迁移，并将中性粒细胞耗竭或阻止其迁移，以确定对RVF病程、发病机制和结局的影响。这项研究完成后，将填补一个关键的空白，了解RVFV如何进入大脑和宿主嗜中性粒细胞的致命性脑炎RVF的发病机制。

 DESCRIPTION (provided by applicant): Understanding the pathogenesis of neurological disease caused by arboviruses is fundamental to the treatment of lethal viral encephalitides using drug or vaccine therapy. Rift Valley Fever is a globally-important emerging zoonotic arboviral disease that presents a significant risk to humans and livestock communities. RVFV infection of humans can result in a spectrum of clinical outcomes, including acute febrile illness, severe hepatic disease, or delayed-onset encephalitis. The mechanisms behind the different human clinical outcomes are undefined and represent a void in our understanding of this emerging viral disease. The long-term goal is to understand the pathophysiologic mechanisms contributing to the spectrum of clinical outcomes after infection with RVFV as well as the immunological response essential for protection against RVF. The overall objectives of this proposal are to determine how neuroinvasion by Rift Valley Fever Virus occurs and the role of the host immune response in the neurological disease and outcome of infection. The central hypothesis for this proposal is that a neutrophil-mediated host inflammatory response in the brain exacerbates neuroinvasion and neurological disease in RVFV-infected rats. The central hypothesis will be addressed with the following Specific Aims: 1) Determine the route of neuroinvasion by RVFV. Since a large gap in knowledge exists as to how RVFV invades the central nervous system, the route of neuroinvasion from the site of infection to the brain will be determined. 2) Determine how neutrophil infiltration into the brain affects neurological disease. Preliminary data suggests that neutrophil recruitment contributes to immune-mediated tissue damage in the brain of infected rats. To test this hypothesis, neutrophil migration into the brain in response to RVFV infection will be measured, and neutrophils will be depleted or blocked from migrating to determine the effect on RVF disease course, pathogenesis and outcome. Upon completion of this study, a critical void will have been filled in the understanding of how RVFV enters the brain and the contribution of host neutrophils to pathogenesis of lethal encephalitic RVF.