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：
8891769
负责人：
Amy L Hartman
金额：
$ 22.86万
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 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8891769
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 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 public health relevance 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（由适用提供）：了解由arbovirus引起的神经系统疾病的发病机理是使用药物或阴道疗法治疗致命的病毒性脑肽的基础。 Rift Valley Fever是一种最重要的新兴人畜共患病，对人类和牲畜群落构成了重大风险。 RVFV感染人类会导致各种临床结局，包括急性发热疾病，严重的肝病或延迟性脑炎。不同人类临床结果背后的机制是不确定的，在我们对这种新兴病毒疾病的理解中代表了一个空白。长期的目标是了解导致RVFV感染后临床结局的病理生理机制，以及防止RVF保护必不可少的免疫学反应。该提案的总体目标是确定裂谷发烧病毒的神经入侵如何以及宿主免疫响应在神经系统疾病和感染结果中的作用。该提案的中心假设是，神经磷脂介导的脑中炎症反应加剧了RVFV感染的大鼠神经浸泡和神经系统疾病。中央假设将以以下特定目的来解决：1）通过RVFV确定神经侵袭的途径。由于关于RVFV如何入侵中枢神经系统的知识存在很大的差距，因此将确定神经侵袭从感染部位到大脑的途径。 2）确定神经磷浸入大脑如何影响神经系统疾病。初步数据表明，神经磷脂募集有助于受感染大鼠大脑的免疫介导的组织损伤。为了检验这一假设，将测量神经磷在RVFV感染中迁移到大脑中，并将中性粒细胞耗尽或阻止迁移，以确定对RVF疾病病程，发病机理和结果的影响。这项研究完成后，对RVFV如何进入大脑以及宿主嗜中性粒细胞对致命性脑脑RVF发病机理的贡献的理解将填补关键空隙。