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) 是一种新兴的蚊媒病毒，在美国引起最致命的虫媒病毒性疾病，病死率高达 75%。然而，EEEV 也在南美洲和中美洲 (SA) 传播，那里许多人接触过受感染的蚊子，但几乎没有疾病证据。流行病学和发病机制研究表明，SA 菌株对人的传染性较差，可能与对 I 型干扰素 (IFN) 的敏感性较高以及 IFN 诱导能力较强有关 骨髓细胞感染后。 2010 年，北美地区与南澳地区 EEE 发病率的主要对比发生了巨大变化，当时拉丁美洲记录的首例人类疫情发生在巴拿马 (PA)。临床疾病与北美地区相似，我们的遗传和流行病学数据表明，自 1986 年以来，地方性 PA EEEV 毒株的传染性和/或毒力有所增加。由于 SA EEEV 载体比 NA 载体更频繁地叮咬人，因此，如果 2010 年 PA 毒株传播到拉丁美洲其他地区，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 PA 毒株的遗传和表型变化对于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实验感染和体外模型相结合，在了解虫媒病毒疾病（包括委内瑞拉马脑炎和基孔肯雅热）的出现方面取得了重大进展。然而，为了应用这些方法来从机理上理解 2010 年 PA EEE 的出现，需要更好的体外和小动物 EEE 模型。目前缺乏此类模型是更好地理解人类 EEE 和开发改进干预措施的主要瓶颈。在这个探索性项目中，我们将利用对 EEE 分子发病机制理解的最新重大进展，开发模型，预测 1984 年与 2010 年 PA EEEV 毒株对人类毒力的差异，有两个具体目标： 1. 测试棉鼠，如果需要，测试各种小鼠品系和仓鼠复制人类疾病的能力，并反映 NA 和先前分离的 SA EEEV 之间感染性/毒力的典型差异。 菌株，并比较这些模型中 1984 年和 2010 年的 PA 菌株。 2. 对 PA 和代表性 NA 和 SA EEEV 菌株进行体外分子发病机制比较研究，以确定人类毒力标记。这些模型将使我们能够检验以下假设：1986 年至 2010 年间 PA EEEV 毒株的遗传变化（包括 3' 非翻译基因组区域）改变了病毒对树突状细胞的感染性和诱导干扰素反应，从而导致病毒具有更大的毒力和感染性。 人类。该开发项目不仅将促进对 EEEV 出现的机制的理解，而且还将促进对甲病毒发病机制的理解，这将导致监测、诊断、治疗和疫苗开发的改进。