The Molecular Basis of VEEV Pathogenesis

VEEV 发病机制的分子基础

• 批准号: 7463181
• 负责人: ILYA V. FROLOV
• 金额: $ 17.85万
• 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: 2008-03-01 至 2009-01-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7463181
• 关键词: 5' Untranslated Regions; Adverse reactions; Aerosols; Affect; Alphavirus; Animals; Antiviral Agents; Antiviral Response; Attenuated; Attenuated Live Virus Vaccine; Binding; Biological Warfare; Biology; Capsid; Capsid Proteins; Categories; Cells; Centers for Disease Control and Prevention (U.S.); Comparative Study; Complementary DNA; Culicidae; Cultured Cells; Data; Development; Disease; Down-Regulation; Elements; Encephalitis; Environment; Epidemic; Equus caballus; Event; Exhibits; Family; Genes; Genetic Transcription; Genome; Goals; Human; Immune response; Immunologic Deficiency Syndromes; Infection; Investigation; Knowledge; Lead; Location; Modification; Molecular; Mutate; Mutation; Nature; Neurologic; North America; Nuclear Export; Nuclear Pore Complex; Numbers; Pathogenesis; Pathogenicity; Pathway interactions; Peptides; Phenotype; Play; Proteins; Public Health; RNA; RNA chemical synthesis; Rate; Recombinants; Research; Role; Structure; Study models; Techniques; Time; Togaviridae; Toxin; Translations; Vaccines; Variant; Viral; Viral Genome; Viral Pathogenesis; Viral Proteins; Virulence; Virulent; Virus; Virus Replication; Western Equine Encephalomyelitis; base; cytokine; design; forest; gene delivery system; genetic manipulation; in vivo; novel; nucleocytoplasmic transport; pathogen; receptor; research study; response; trafficking; virus genetics; virus host interaction; virus pathogenesis

DESCRIPTION (provided by applicant): The Alphavirus genus in the Togaviridae family includes a number of important human and animal pathogens, including Venezuelan (VEEV), eastern (EEEV) and western equine encephalitis (WEEV) viruses. The latter constitute a serious public health threat in the US, because they continuously circulate in nature and have the ability to cause fatal disease in humans and horses. In addition, EEEV, WEEV and, in particular, VEEV have the potential for use by terrorists and as biological warfare agents. In spite of the continuous threat of VEEV epidemics, the biology of VEEV, in particular the molecular basis of its high virulence, has been studied less intensively than that of other alphaviruses. It was believed that Sindbis (SINV) and Semliki Forest (SFV) viruses, which are dramatically less pathogenic than VEEV, represent good models for studying the mechanism of VEEV replication and virus-host interactions. However, results from recent comparative studies with VEEV and SINV suggested that VEEV replication and its pathogenesis strongly differ from those previously described for SINV. Hence, a great part of our knowledge about SINV biology cannot be directly applied to VEEV. Our preliminary studies strongly suggested that the VEEV capsid plays critical roles in inhibiting both nucleocytoplasmic trafficking and cellular transcription and, thus, downregulation of the innate immune response. Our results also suggested the 5'UTR of the VEEV genome is one of the important determinants of viral pathogenesis. Therefore, the proposed research is aimed at further understanding the functions of VEEV capsid and 5'UTR in virus replication, and in determining virus pathogenesis at different levels. The proposed experiments are organized into three aims. In specific aim 1, we intend to define functioning of VEEV capsid in the nucleocytoplasmic transport inhibition. In specific aim 2, we will perform a detailed investigation of the effects of the strain-specific mutations in the 5'UTR sequence on VEEV replication and pathogenesis on molecular and cellular levels; and in specific aim 3, we will apply already available information and new data that will be generated in our proposed experiments to develop new, highly attenuated strains of VEEV for vaccine applications. The specific aims represent three independent lines of research, but they are expected to generate complementary data. The results of this study will also be applicable to other encephalitogenic alphaviruses, such as EEEV and WEEV. PUBLIC HEALTH RELEVANCE: Alphaviruses comprise a group of widely distributed human and animal pathogens; some of them induce highly debilitating diseases and represent a serious public health threat in the US. The goal of this application is to understand the role of viral proteins in modification of the intracellular environment during virus replication and development of new, highly attenuated, live vaccines against encephalitogenic alphaviruses.

描述（由申请人提供）：Togaviridae家族中的α病毒属包括许多重要的人类和动物病原体，包括委内瑞拉（VEEV），东部（EEEV）和西部马脑炎（WEEV）病毒。后者在美国构成了严重的公共卫生威胁，因为它们在本质上不断流通，并具有在人类和马匹中引起致命疾病的能力。此外，EEEV，WEEV，尤其是Veev有可能被恐怖分子和作为生物战的代理商使用。尽管VEEV流行病的持续威胁，但VEEV的生物学，特别是其高毒力的分子基础，对其他α病毒的研究却少于研究。人们认为，与VEEV相比，Sindbis（Sinv）和Semliki Forest（SFV）病毒的致病性较小，代表了研究VEEV复制机制和病毒 - 霍斯特相互作用机制的好模型。然而，最近与VEEV和SINV的比较研究的结果表明，VEEV复制及其发病机理与先前描述的SINV有很大不同。因此，我们对SINV生物学的了解的很大一部分不能直接应用于Veev。我们的初步研究强烈表明，VEEV衣壳在抑制核质流量和细胞转录方面起着关键作用，因此，降低了先天免疫反应。我们的结果还表明，VEEV基因组的5'UTR是病毒发病机理的重要决定因素之一。因此，拟议的研究旨在进一步理解Veev Capsid和5'UTR在病毒复制中的功能，以及在不同水平上确定病毒发病机理。提出的实验分为三个目标。在特定的目标1中，我们打算定义Veev capsid在核质转运抑制中的功能。在特定的目标2中，我们将对5'UTR序列中应变特异性突变对VEEV复制和发病机理对分子和细胞水平的发病机理的影响进行详细研究；在特定的目标3中，我们将应用已在我们提出的实验中生成的已经可用的信息和新数据，以开发新的，高度减弱的VEEV菌株以用于疫苗应用。具体目的代表了三个独立的研究线，但预计它们将产生互补数据。这项研究的结果也将适用于其他脑源性α病毒，例如EEEV和WEEV。 公共卫生相关性：α病毒包括一组广泛分布的人类和动物病原体；他们中的一些人引起了高度令人衰弱的疾病，并代表了美国的严重公共卫生威胁。该应用的目的是了解病毒蛋白在修饰细胞内环境中的作用，在病毒复制和开发新的，高度衰减的实时疫苗针对脑源性α病毒。