Mechanisms of Neuropathogenic Rift Valley Fever in a Novel Rat Model

 描述(申请人提供)：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疗法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出现的人畜共患病，对人类和牲畜社区构成重大风险。人感染RVFV可导致一系列临床结果，包括急性发热性疾病， 严重的肝病或迟发性脑炎。人类不同临床结果背后的机制尚不确定，代表着我们对这种新出现的病毒疾病的理解空白。长期目标是了解感染RVFV后影响临床结果的病理生理学机制，以及预防RVF所必需的免疫反应。这项建议的总体目标是确定裂谷热病毒如何发生神经入侵，以及宿主免疫反应在神经系统疾病和感染结果中的作用。这一提议的中心假设是，脑部中性粒细胞介导的宿主炎症反应加剧了RVFV感染大鼠的神经侵袭和神经系统疾病。中心假说的具体目的如下：1)确定RVFV侵袭神经的途径。由于有关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)确定中性粒细胞渗入大脑如何影响神经系统疾病。初步数据表明，中性粒细胞募集有助于感染大鼠脑内免疫介导的组织损伤。为了验证这一假设，我们将测量RVFV感染后中性粒细胞迁移到大脑中的情况，并将中性粒细胞耗尽或阻止迁移，以确定对RVF病程、发病机制和预后的影响。这项研究完成后，在了解RVFV如何进入大脑以及宿主中性粒细胞在致死性脑性RVF发病机制中的作用方面，将填补一个关键的空白。

 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.