Mechanisms of evasion of the innate and adaptive immune responses to filoviruses

丝状病毒先天性和适应性免疫反应的逃避机制

• 批准号: 8653056
• 负责人: Christopher F Basler
• 金额: $ 200万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8653056
• 关键词: Address; Antiviral Agents; Biochemical; Biology; Categories; Cell Communication; Cell Maturation; Cell physiology; Characteristics; Coagulation Process; Coupled; Data; Democratic Republic of the Congo; Dendritic Cell Pathway; Dendritic Cells; Development; Disease Outcome; Ebola virus; Family member; Filovirus; Frankfurt-Marburg Syndrome Virus; Frequencies; Gene Expression; Generations; Genetic; Genetic Transcription; Gold; Head; Human; Immune; Immune System Diseases; Immune response; Immunity; Infection; Inflammation; Inflammatory Response; Integration Host Factors; Interferon Type I; Interferon-alpha; Interferons; Lead; Lymphocyte; Macaca; Methods; Modeling; Molecular; Mutation; Natural Immunity; Nuclear; Outcome; Paralysed; Pathogenesis; Pathway interactions; Phenotype; Phosphotransferases; Play; Population; Production; Proteins; Publishing; RNA Viruses; Receptor Signaling; Recombinants; Research Personnel; Role; Signal Transduction; Subfamily lentivirinae; System; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Viral; Viral Hemorrhagic Fevers; Viral Physiology; Virulence; Virus; Virus Diseases; Work; adaptive immunity; alpha Karyopherins; apoptosis in lymphocytes; base; defined contribution; experience; functional status; genetic manipulation; in vivo; insight; monocyte; mutant; nonhuman primate; pathogen; prevent; programs; public health relevance; response; restoration; structural biology; therapy development; trafficking

DESCRIPTION (provided by applicant): The filoviruses, the ebolaviruses (EBOVs) and marburgviruses (MARVs), are category A priority pathogens that cause highly lethal hemorrhagic fever in humans with fatality rates approaching 90 percent (20). The well-characterized non-human primate models of filovirus, particularly Zaire EBOV (ZEBOV), infection are now the best developed models of viral hemorrhagic fever. Despite their recognized importance and the availability of good models, approved therapeutic approaches are lacking, due in part to an incomplete understanding of pathogenesis. Immune dysfunction appears to be a major component of filoviral hemorrhagic fever which is characterized by suppressed type I interferon (IFN) responses, excessive inflammation and coagulation, impaired dendritic cell (DC) function and massive apoptosis of lymphocytes. However, many details remain poorly defined and strategies to overcome dysregulated immunity are lacking. This Program addresses the hypothesis that filoviral IFN-antagonist proteins play a central role in the immune dysregulation characteristic of filoviral infection. It will test this hypothesis and define immunological mechanisms contributing to pathogenesis. This will be accomplished through the efforts of three highly integrated projects that each addresses a distinct objective. Project 1 wil define the structural/biochemical basis for IFN-antagonist-host factor interactions and identify loss of interaction mutations. Using a highly efficient lentivirus expression system, the impact of IFN-antagonist expression on DC maturation and function will be defined. Finally, through the use of the loss of interaction mutants and gene expression knockdown methods, the impact of the IFN-antagonists on specific DC pathways will be defined. Project 2 will address the hypotheses that that the disrupted maturation of DCs induced by EBOV and MARV infection will lead to impaired T cell activation and aberrant/absent T cell function and that the mechanisms of the filoviral IFN-antagonist proteins make key contributions to these outcomes. Project 3 will characterize the phenotype and functional status of dendritic cells and lymphocytes during infection, testing whether these populations are dysregulated by filovirus infection and define the contribution of IFN-antagonist functions to in vivo immune dysregulation. These efforts will span structural biology, innate immune signaling studies, DC-T cell interaction analyses and characterization of immune responses in filovirus-infected macaques. Their successful completion will provide unprecedented insight into the immune mechanisms that contribute to a viral hemorrhagic fever.

描述(申请人提供)：丝状病毒，埃博拉病毒(EBOV)和马尔堡病毒(MARV)，是A类优先病原体，可导致人类高度致命的出血热，病死率接近90%(20)。特征明确的非人灵长类丝状病毒模型，特别是扎伊尔EBOV(ZEBOV)感染，现在是最发达的病毒性出血热模型。尽管公认的重要性和良好的模型的可用性，批准的治疗方法是缺乏的，部分原因是对发病机制的不完全了解。免疫功能障碍是丝状病毒出血热的一个主要组成部分，其特征是I型干扰素反应受到抑制，过度炎症和凝血，树突状细胞(DC)功能受损和淋巴细胞大量凋亡。然而，许多细节仍然定义不清，缺乏克服免疫失调的策略。本计划提出的假设是，丝状病毒干扰素拮抗剂蛋白在丝状病毒感染的免疫失调特征中发挥核心作用。它将检验这一假设并定义 免疫机制在发病机制中的作用。这将通过三个高度整合的项目的努力来实现，每个项目都针对不同的目标。项目1将定义干扰素-拮抗剂-宿主因子相互作用的结构/生化基础，并确定相互作用突变的丢失。使用高效的慢病毒表达系统， 干扰素拮抗剂的表达对DC成熟和功能的影响将被明确。最后，通过使用相互作用缺失突变体和基因表达敲除方法，确定干扰素拮抗剂对特定DC途径的影响。项目2将解决这样的假设，即EBOV和MARV感染诱导的DC成熟中断将导致T细胞激活受损和T细胞功能异常/缺失，并且丝状病毒干扰素拮抗剂蛋白的机制对这些结果起关键作用。项目3将描述感染期间树突状细胞和淋巴细胞的表型和功能状态，测试这些群体是否受到丝状病毒感染的失调，并确定干扰素拮抗剂功能在体内免疫失调中的作用。这些工作将涵盖结构生物学、先天免疫信号研究、DC-T细胞相互作用分析以及丝状病毒感染猕猴免疫反应的表征。它们的成功完成将提供对导致病毒性出血热的免疫机制的前所未有的洞察。