Molecular Pathogenesis of Ebolavirus Infection

埃博拉病毒感染的分子发病机制

• 批准号: 7936222
• 负责人: YOSHIHIRO KAWAOKA
• 金额: $ 44.6万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-26 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7936222
• 关键词: Affect; Amino Acids; Animal Model; Antiviral Agents; Antiviral Response; Binding Proteins; Biological; Categories; Cells; Chimeric Proteins; Coagulation Process; Data; Development; Dissection; Emerging Communicable Diseases; Endothelial Cells; Event; Fibrinolysis; Figs - dietary; Generations; Genes; Genome; Glycoproteins; Goals; Human; Immune response; In Vitro; Individual; Infection; Infectious Diseases Research; Inflammatory; Interferons; Interleukin-6; Knowledge; Licensing; Messenger RNA; Modification; Molecular; Mus; Mutation; NP protein; National Institute of Allergy and Infectious Disease; Nucleotides; Pathogenesis; Pathogenicity; Pathway interactions; Play; Population; Proteins; Reading Frames; Research; Rodent; Role; Serum; Signal Pathway; System; Testing; Therapeutic; Transcription Factor AP-1; Umbilical vein; Up-Regulation; Vaccines; Viral; Viral Hemorrhagic Fevers; Virion; Virus; Virus Replication; base; biodefense; combat; cytokine; defined contribution; drug development; improved; in vivo; insight; mRNA Expression; macrophage; mortality; mouse model; mutant; nonhuman primate; pathogen; positional cloning; programs; receptor binding; response; virus classification

Ebolaviruses and the closely related Marburgviruses continue to pose a lethal threat to human populations worldwide, especially given their potential use as bioweapons and the lack of effective vaccines or antiviral drugs to combat their pathogenicity and spread. The long-term goal of this proposal is to improve understanding of the extreme pathogenicity of Ebolaviruses by focusing on mechanisms that likely contribute to the classification of this virus as a "Category A Priority" pathogen. Studies in this proposal assess the significance of the secreted glycoprotein (sGP); editing of the sGP mRNA causes a reading frame shift, resulting in expression of the GP receptor-binding/fusion protein. Our preliminary data suggest that sGP expression and sGP mRNA editing have important roles in Ebolavirus pathogenicity, most likely by promoting efficient viral replication via suppression of host antiviral responses. This hypothesis will be tested by characterizing Ebolavirus sGP mutants generated with reverse genetics and by studying their function in vitro. By advancing knowledge of likely determinants of Ebolavirus pathogenicity, we expect to provide compelling new rationales for vaccine and targeted drug development.

埃博拉病毒和密切相关的马尔堡病毒继续对全世界人口构成致命威胁，特别是考虑到它们可能用作生物武器，而且缺乏有效的疫苗或抗病毒药物来对抗其致病性和传播。该提案的长期目标是通过关注可能有助于将该病毒归类为“A类优先”病原体的机制，提高对埃博拉病毒极端致病性的认识。本提案中的研究评估了分泌型糖蛋白（sGP）的意义; sGP mRNA的编辑导致阅读移码，导致GP受体结合/融合蛋白的表达。我们的初步数据表明，sGP表达和sGP mRNA编辑在埃博拉病毒致病性中具有重要作用，最有可能是通过抑制宿主抗病毒反应来促进有效的病毒复制。这一假设将通过表征反向遗传学产生的埃博拉病毒sGP突变体并通过研究其体外功能来验证。通过进一步了解埃博拉病毒致病性的可能决定因素，我们希望为疫苗和靶向药物开发提供令人信服的新理论基础。