VEE Virus Infection on the Mosquito Vector

蚊子载体上的 VEE 病毒感染

• 批准号: 7541802
• 负责人: Scott C Weaver
• 金额: $ 33.98万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7541802
• 关键词: Aedes; Affect; Agriculture; Alphavirus; Americas; Amino Acids; Animal Diseases; Apical; Arboviruses; Attention; Binding; Biological; Biological Assay; Biological Models; Brush Border; Cells; Culicidae; Development; Disease; Disease Outbreaks; Epidemic; Epithelial Cells; Epithelial Receptor Cell; Epithelium; Equus caballus; Event; Gene Mutation; Genes; Genetic Determinism; Glycoproteins; Goals; Human; Immunodominant Epitopes; Individual; Infection; Location; Mediating; Methods; Midgut; Molecular Genetics; Mutation; Ochlerotatus; Organ; Pattern; Phenotype; Population; Process; Proteins; Replicon; Research; Rodent; Salivary Glands; Serotyping; Sodium Chloride; South America; Surface; Testing; Texas; Tissues; Togaviridae; Vaccines; Variant; Venezuelan Equine Encephalitis Virus; Viral; Viremia; Virion; Virulence; Virus; Virus Diseases; Work; enzootic; epizootic; novel strategies; oral infection; particle; pathogen; positional cloning; research study; tool; transmission process; vector; vector mosquito; viral RNA; virus genetics; weapons

DESCRIPTION (provided by applicant): The efficiency of mosquito infections by arthropod-borne viruses (arboviruses) can be an important determinant of disease emergence. An example is Venezuelan equine encephalitis virus (VEEV), an important, reemerging alphavirus pathogen of humans and equines in the New World, and also a potent biological weapon. Our recent work has demonstrated that enzootic, sylvatic, rodent-borne, subtype ID VEEV strains periodically adapt for efficient equine replication and high titer viremia induction to generate epidemic strains and amplification cycles that spillover to infect humans. These adaptation events are mediated by mutations that alter amino acids in the E2 envelope glycoprotein, an important component of spikes on the virion surface. In addition, the E2 genes of most subtype IAB and IC epidemic strains also enhance their ability to infect the epidemic mosquito vector, Aedes (Ochlerotatus) taeniorhynchus, a salt marsh species that has been implicated in transmission during most major VEE outbreaks ranging from northern South America to Texas. Either adaptation or the pre-existing ability of VEEV to utilize this vector (possibly due to selection for equine amplification) may therefore be a major determinant of epidemic transmission and outbreak magnitude. This virus-vector interaction is also an ideal model system to advance understanding of natural alphavirus-mosquito interactions because it has been thoroughly evaluated using a variety of viral strains and mosquito populations. We will further characterize infection of Ae. taeniorhynchus by both enzootic and epidemic VEEV strains in order to understand more completely the mechanisms of viral adaptation to this vector. The enhanced epidemic VEEV strain infection, dissemination in and/or transmission by Ae. taeniorhynchus will be examined using a unique set of fluorescent protein- expressing enzootic and epidemic VEEV replicon particles and viruses. Combined with traditional and molecular genetic methods, these tools will be used to examine infection of the mosquito midgut, believed to be the portal of entry, as well as downstream target tissues and organs including the salivary glands. These viruses and replicon particles will also be used to characterize the barriers to infection and dissemination that are overcome by epidemic VEEV strains for efficient transmission, and reverse genetic approaches will identify the determinants of the efficient infection VEEV phenotype. The results of this project will enhance understanding of natural interactions between alphaviruses and mosquito vectors, a research topic that has received little attention in recent years. It will also add to our understanding of the mechanisms of epidemic VEEV emergence and provide new viral and host targets for the development of safer vaccines and novel strategies to interrupt arbovirus transmission.This project will examine the process of infection of mosquito vectors by Venezuelan equine encephalitis virus (VEEV), an important emerging virus that continues to threaten the Americas including the U.S. The mechanisms and genetic determinants of mosquito infection will be determined to explain why certain mosquitoes are efficient vectors of some but not other VEEV strains. The results will add to our understanding of the mechanisms of epidemic VEEV emergence and provide new viral and host targets for the development of safer vaccines and novel strategies to interrupt transmission.

描述（由申请人提供）：节肢动物传播的病毒（虫媒病毒）感染蚊子的效率可能是疾病出现的重要决定因素。委内瑞拉马脑炎病毒（VEEV）就是一个例子，它是新世界中重新出现的一种重要的人类和马科甲病毒病原体，也是一种有效的生物武器。我们最近的工作表明，地方性、森林性、啮齿类动物传播的 ID VEEV 亚型毒株会定期适应马的有效复制和高滴度病毒血症诱导，从而产生流行毒株和扩增循环，从而溢出感染人类。这些适应事件是由改变 E2 包膜糖蛋白中氨基酸的突变介导的，E2 包膜糖蛋白是病毒颗粒表面刺突的重要组成部分。此外，大多数 IAB 和 IC 亚型流行毒株的 E2 基因还增强了它们感染流行蚊媒带纹伊蚊的能力，这是一种盐沼物种，在从北部到南部的大多数主要 VEE 爆发期间与传播有关。美国到德克萨斯州。因此，VEEV 的适应或利用该载体的预先存在的能力（可能是由于马扩增的选择）可能是流行病传播和爆发规模的主要决定因素。这种病毒-载体相互作用也是促进对天然甲病毒-蚊子相互作用的理解的理想模型系统，因为它已经使用各种病毒株和蚊子种群进行了彻底评估。我们将进一步表征伊蚊的感染。通过地方性和流行性 VEEV 菌株对带喙龙进行了研究，以便更全面地了解病毒对该载体的适应机制。流行性 VEEV 菌株感染、伊蚊传播和/或传播增强。将使用一套独特的表达荧光蛋白的地方性和流行性 VEEV 复制子颗粒和病毒来检查带喙龙。与传统和分子遗传学方法相结合，这些工具将用于检查蚊子中肠（被认为是进入的门户）以及下游目标组织和器官（包括唾液腺）的感染情况。这些病毒和复制子颗粒还将用于表征流行性 VEEV 毒株克服的感染和传播障碍，以实现有效传播，而反向遗传方法将确定有效感染 VEEV 表型的决定因素。该项目的结果将增强对甲病毒和蚊媒之间自然相互作用的理解，这是近年来很少受到关注的研究课题。它还将增加我们对流行性VEEV出现机制的理解，并为开发更安全的疫苗和阻断虫媒病毒传播的新策略提供新的病毒和宿主靶标。该项目将研究委内瑞拉马脑炎蚊媒感染的过程病毒（VEEV），一种重要的新兴病毒，继续威胁包括美国在内的美洲地区。将确定蚊子感染的机制和遗传决定因素，以解释为什么某些蚊子是某些而非其他 VEEV 的有效载体菌株。这些结果将加深我们对流行性 VEEV 出现机制的理解，并为开发更安全的疫苗和阻断传播的新策略提供新的病毒和宿主靶标。