Mechanisms of Neuropathogenic Rift Valley Fever in a Novel Rat Model

新型大鼠模型中神经致病性裂谷热的机制

基本信息

批准号：
9002103
负责人：
Amy L Hartman
金额：
$ 19.03万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9002103
关键词：
Acute Address Aerosols Affect Africa Americas Animal Model Animals Arboviruses Area Bite Blood Brain Breathing Central Nervous System Viral Diseases Clinical Communities Country Culicidae Data Disease Disease Outbreaks Disease Outcome Dose Economics Encephalitis Epidemic Europe Experimental Models Exposure to Fever Goals Health Human IL8RB gene Immune Immune response Immunocompetent Incidence Infection Infiltration Inflammatory Inflammatory Response Invaded Knowledge Life Liver diseases Livestock Lymphocyte Measures Mediating Middle East Modeling Nervous System Trauma Neuraxis Neurological outcome Neurons Neuropathogenesis Neutrophil Infiltration Neutrophilia Olfactory Epithelium Outcome Pathogenesis Pharmacotherapy Play Prevention Public Health Rattus Replicon Reporter Genes Rift Valley Fever Rift Valley fever virus Risk Role Route Ruminants Serum Site Testing Therapeutic Therapeutic Uses Tissues Vaccine Therapy Vaccines Viral Antigens Viral Encephalitis Viremia Virulent Virus Virus Diseases Virus Replication Work arbovirus disease base brain tissue cytokine end stage disease enzootic epizootic fMet-Leu-Phe receptor human disease human morbidity human mortality in vivo imaging migration nervous system disorder neurovirulence neutrophil nonhuman primate novel olfactory bulb olfactory sensory neurons particle pathogen prevent response socioeconomics vector mosquito

项目摘要

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.

描述（由申请人提供）：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命病毒性脑炎的基础。裂谷热是一种全球重要的新兴人畜共患虫媒病毒疾病，对人类构成重大风险。人类感染RVFV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的不同人类临床结果背后的机制尚不清楚，并且我们对这种新出现的病毒性疾病的理解存在空白。长期目标是了解导致临床谱系的病理生理机制。感染 RVFV 后的结果以及预防 RVF 所必需的免疫反应该提案的总体目标是确定裂谷热病毒的神经侵袭如何发生以及宿主免疫反应在神经系统疾病和疾病中的作用。该提议的中心假设是，中性粒细胞介导的大脑中的宿主炎症反应会恶化 RVFV 感染大鼠的神经侵袭和神经系统疾病。该中心假设将通过以下具体目标来解决：1）确定途径。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，中性粒细胞募集会导致感染大鼠大脑中免疫介导的组织损伤。测量，中性粒细胞将被耗尽或阻止其迁移，以确定对裂谷热病程、发病机制和结果的影响。这项研究完成后，将填补一个关键空白。了解 RVFV 如何进入大脑以及宿主中性粒细胞对致命性脑炎 RVF 发病机制的贡献。