Eastern Equine Encephalitis Emergence in Panama

巴拿马出现东部马脑炎

• 批准号: 8927903
• 负责人: Scott C Weaver
• 金额: $ 24.53万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-22 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8927903
• 关键词: Aedes; Alphavirus; American; Americas; Animal Model; Animals; Behavior; Biological Assay; Bite; Case Fatality Rates; Cell Culture Techniques; Central America; Chikungunya virus; Clinical; Cotton Rats; Culicidae; Data; Dendritic Cells; Development; Diagnosis; Diagnostic; Disease; Disease Outbreaks; Eastern Equine Encephalitis Virus; Eastern Equine Encephalomyelitis; Epidemiology; Equus caballus; Evolution; Genetic; Genome; Glycoproteins; Goals; Hamsters; Human; In Vitro; Incidence; Infection; Interferon Type I; Interferons; Intervention; Laboratories; Latin America; Lead; Measures; Modeling; Molecular; Mouse Strains; Mutation; Myeloid Cells; Neurologic; North America; Panama; Panamanian; Pathogenesis; Pathogenicity; Phenotype; Preventive Intervention; Public Health; Reporting; Rodent; Role; Series; Seroprevalences; South America; Testing; Variant; Venezuelan Equine Encephalitis Virus; Venezuelan Equine Encephalomyelitis; Viral; Viremia; Virulence; Virus; Virus Diseases; arbovirus disease; chikungunya; comparative; enzootic; epidemiologic data; epizootic; exposed human population; genetic approach; human disease; improved; in vitro Model; public health relevance; response; reverse genetics; therapeutic development; therapy development; vaccine development; vector; vector mosquito

 DESCRIPTION (provided by applicant): Eastern equine encephalitis virus (EEEV), an emerging mosquito-borne virus, causes the deadliest arboviral disease in the U.S., with case-fatality rates up to 75%. However, EEEV also circulates throughout South and Central America (SA), where many people are exposed to infected mosquitoes yet with little evidence of disease. Epidemiologic and pathogenesis studies suggest that SA strains are poorly infectious for people, possibly related to higher sensitivity to type I interferon (IFN) and greater IFN induction following infection of myeloid cells. The major contrast in EEE incidence in NA vs. SA changed dramatically in 2010, when the first human outbreak ever documented in Latin America occurred in Panama (PA). Clinical disease was similar to that seen in NA, and our genetic and epidemiologic data indicate that an enzootic PA EEEV strain increased its infectivity and/or virulence since 1986. Because SA EEEV vectors bite people more frequently than NA vectors, this change in EEEV virulence could have major public health implications if the 2010 PA strain spreads to other parts of Latin America, or if similar viral changes occur in the region. Understanding the genetic and phenotypic changes in the 2010 PA strain is therefore critical to our long-term goal of reducing arboviral disease. Recently, our reverse genetic approaches combined with experimental infections of animal and in vitro models led to major advances in understanding arboviral disease emergence, including Venezuelan equine encephalitis and chikungunya. However, to apply these approaches to gain a mechanistic understanding the 2010 PA EEE emergence, better in vitro and small animal EEE models are needed. The lack of such models currently represents the major bottleneck to a better understanding of human EEE and developing improved interventions. In this exploratory project, we will exploit recent, major advances in the understanding of EEE molecular pathogenesis to develop models that predict differential human virulence of 1984 vs. 2010 PA EEEV strains using 2 specific aims: 1. Test cotton rats, and if needed, a variety of mouse strains and hamsters for their ability to reproduce human-like disease and to mirror the typical differences in infectivity/virulence between NA and previously isolated SA EEEV strains, and to compare 1984 and 2010 PA strains in these models. 2. Perform comparative in vitro molecular pathogenesis studies of PA and representative NA and SA EEEV strains to identify markers of human virulence. These models will allow us to test the hypothesis that genetic changes in PA EEEV strains between 1986-2010, including in the 3' untranslated genome region, altered the virus' infectivity for dendritic cells and the induction of interferon responses, resulting in greater virulence and infectivity for humans. This developmental project will advance the mechanistic understanding not only of EEEV emergence, but also of alphavirus pathogenesis, which will lead to improved surveillance, diagnostics, treatment and vaccine development.

 描述（由申请人提供）：东部马脑炎病毒（EEEV），一种新出现的蚊媒病毒，在美国引起最致命的虫媒病毒病，病死率高达75%然而，EEEV也在南美洲和中美洲（SA）传播，许多人暴露于受感染的蚊子，但几乎没有疾病的证据。流行病学和发病机制研究表明，SA菌株对人的感染性差，可能与对I型干扰素（IFN）的敏感性较高和IFN诱导作用较大有关 骨髓细胞感染后。2010年，当拉丁美洲有记录的第一次人类暴发发生在巴拿马（PA）时，NA与SA的疟疾发病率的主要对比发生了巨大变化。临床疾病是类似的NA，我们的遗传和流行病学数据表明，自1986年以来，地方性PA EEEV菌株增加其感染性和/或毒力。由于SA EEEV媒介比NA媒介更频繁地叮咬人，如果2010年PA毒株传播到拉丁美洲的其他地区，或者如果该地区发生类似的病毒变化，EEEV毒力的这种变化可能会对公共卫生产生重大影响。因此，了解2010年PA菌株的遗传和表型变化对我们减少虫媒病毒疾病的长期目标至关重要。最近，我们的反向遗传方法与动物和体外模型的实验感染相结合，导致在了解虫媒病毒疾病出现方面取得了重大进展，包括委内瑞拉马脑炎和基孔肯雅热。然而，为了应用这些方法来获得对2010年PA出现的机制的理解，需要更好的体外和小动物模型。目前，缺乏这种模式是更好地了解人类健康和制定更好的干预措施的主要瓶颈。在这个探索性的项目中，我们将利用最近的，主要的进展，在理解的分子发病机制，开发模型，预测差异人类毒力的1984年与2010年PA EEEV株使用2个特定的目标：1。测试棉鼠，如果需要，测试各种小鼠品系和仓鼠复制类人疾病的能力，并反映NA和先前分离的SA EEEV毒株之间感染性/毒力的典型差异，并在这些模型中比较1984年和2010年PA毒株。2.对PA和代表性NA和SA EEEV毒株进行体外分子致病性比较研究，以鉴定人类毒力标志物。这些模型将使我们能够检验以下假设：1986-2010年期间PA EEEV毒株的遗传变化，包括3'非翻译基因组区域的遗传变化，改变了病毒对树突状细胞的感染性和干扰素应答的诱导，导致更大的毒力和感染性。 人类该开发项目不仅将促进对EEEV出现的机制理解，还将促进对甲病毒发病机制的理解，这将导致改善监测，诊断，治疗和疫苗开发。