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）：节肢动物传播病毒（arbovirus）感染蚊子感染的效率可能是疾病出现的重要决定因素。一个例子是委内瑞拉马脑炎病毒（VEEV），这是新世界中人类和马的α病原体的重要，也是一种有效的生物武器。我们最近的工作表明，Enzootic，Sylvatic，啮齿动物，亚型ID VEEV菌株定期适应有效的马复制和高滴度的病毒性诱导，从而产生流行性菌株和扩增循环，从而溢出到感染人类。这些适应事件是通过改变E2包膜糖蛋白（病毒座表面上的尖峰的重要组成部分）突变的突变来介导的。此外，大多数亚型IAB和IC流行菌株的E2基因还增强了其感染流行病蚊子载体的能力，艾德斯（Ochlerotatus）taeniorhynchus，这是一种盐沼（Salt Marsh），这是一种在大多数重大疫苗中涉及从北部美国北部到达德克萨斯州的大多数主要vee爆发。因此，VEEV使用该载体的适应性或先前存在的能力（可能是由于对马的选择引起的），可能是流行病传播和爆发幅度的主要决定因素。这种病毒矢量相互作用也是一种理想的模型系统，可以提高对天然α-病毒 - 摩斯奎特相互作用的了解，因为它已经使用多种病毒株和蚊子种群对其进行了彻底的评估。我们将进一步表征AE的感染。 taeniorhynchus通过enzootic和流行病菌株，以便更完全了解病毒适应该载体的机制。增强的流行性VEEV菌株感染，AE传播和/或传播。 Taeniorhynchus将使用一组独特的荧光蛋白表达enzootic和流行病的Veev复制子颗粒和病毒检查。结合传统和分子遗传学方法，这些工具将用于检查蚊子中肠感染，据信是进入的门户，以及包括唾液腺在内的下游靶组织和器官。这些病毒和复制子颗粒还将用于表征感染和传播的障碍，这些障碍通过流行病的VEEV菌株来有效传播，而反向遗传方法将确定有效的感染VEEV表型的决定因素。该项目的结果将增强对α病毒与蚊子矢量之间自然相互作用的理解，近年来，研究主题很少受到关注。这也将增加我们对流行病的出现机制的理解，并为开发更安全的疫苗和中断中断急症的新型疫苗和新型策略提供新的病毒和宿主目标。该项目将研究委内瑞拉武器何种象征性emerius（VEEV）的蚊子媒介的感染过程，包括委内瑞拉的赤道病毒机制，包括持续的emerues，该机制是涉及持续的emering ver in Contiment in Contress，该机构涉及该机制，该依次促进了该机制，该机构构成了该机制，该机构构成了延续的依恋仪式，以使其能够促成延续的依恋范围，以至于促进了该机制，以至于促进了范围的范围，以至于该剂量促进了该机制，以至于促进了延续范围的范围。将确定蚊子感染的决定因素，以解释为什么某些蚊子是某些但不是其他VEEV菌株的有效向量。结果将增加我们对流行病出现机制的理解，并为开发更安全的疫苗和中断传播的新策略提供了新的病毒和宿主目标。