Neuroprotective anti-inflammatory drugs as a novel combination therapy for neurological Rift Valley Fever

项目摘要/摘要 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病毒性脑炎。裂谷热(RVF)是全球重要的 新出现的蚊子传播疾病，对人类和牲畜社区构成重大风险。 由于蚊子媒介的普遍存在，全球传播的可能性很高，而蚊子的出现将导致 相当大的经济损失(由于农业的影响)以及恐惧和焦虑(由于人类 疾病)。由RVFV引起的临床疾病中最少被研究的是脑炎，它会导致长期的 存活者的发病率以及50%有神经系统症状的患者的死亡率。这项建议是有根据的 根据我们初步数据中的三个科学发现：1)有合适的脑病动物模型 感染野生型RVFV毒株后；2)细胞因子、趋化因子和基质的过度产生 金属蛋白酶(MMPs)与神经系统疾病的发病相关；3)抗病毒治疗 治疗药物法维拉韦是必要的，但不足以保护动物免受致命的神经系统疾病的伤害。 综上所述，这项建议的目的是了解细胞因子和基质金属蛋白酶介导的宿主的作用 RVF诱导的神经性疾病的炎症反应，最终目标是设计治疗方案 预防神经病理的干预措施。我们将通过三个相辅相成的具体目标来实现这一目标： 在目标1中，我们将确定细胞因子和MMPs调节RVF CNS的动力学机制 发炎。AIM 2将开发新的体外建模系统来定义RVFV-CNS细胞相互作用和 筛选治疗候选者。AIM 3将在相关的动物模型中测试新的治疗方案。这 该提案将有助于理解免疫病理学对RVF神经疾病的贡献。 重要的是，我们将确定一种暴露后治疗方案，以防止神经性RVF。这 这项提议是在这种新出现的病原体流行的情况下迈出的关键一步。

PROJECT SUMMARY/ABSTRACT Understanding the pathogenesis of neurological disorders caused by arboviruses is fundamental to the treatment of viral encephalitis using drug or vaccine therapy. Rift Valley Fever (RVF) is a globally-important emerging mosquito-transmitted disease that presents a significant risk to humans and livestock communities. The potential for global spread is high due to the pervasive mosquito vectors, and emergence would cause considerable economic damage (due to the agricultural impact) as well as fear and anxiety (due to human illness). The most understudied clinical disease caused by RVFV is encephalitis, which causes long-term morbidity in survivors as well as death in 50% of patients with neurological symptoms. This proposal is founded upon 3 scientific findings from our preliminary data: 1) There are appropriate encephalitic disease animal models after infection with a wild-type virulent strain of RVFV; 2) Overproduction of cytokines, chemokines, and matrix metalloproteinases (MMPs) correlates with neurological disease onset; and 3) Treatment with the antiviral therapeutic drug favipiravir is necessary but not sufficient to protect animals from lethal neurological disease. Taken together, the objective of this proposal is to understand the role of cytokine and MMP-mediated host inflammatory response in RVF-induced neurological disease, with the ultimate goal of designing therapeutic interventions to prevent neuropathology. We will address this objective using three complementary specific aims: In Aim 1, we will determine the kinetic mechanisms by which cytokines and MMPs modulate RVF CNS inflammation. Aim 2 will develop novel in vitro modeling systems to define RVFV-CNS cell interactions and screen therapeutic candidates. Aim 3 will test novel therapeutic regimens in a relevant animal model. This proposal will result in an understanding of the contribution of immunopathology to RVF neurological disease. Importantly, we will have identified a post-exposure treatment regimen to protect from neurological RVF. This proposal represents a critical step in the event of an epidemic of this emerging pathogen.