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

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：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，可引起人类高致死性出血热，死亡率接近 90% (20)。已充分表征的丝状病毒非人类灵长类动物模型，特别是扎伊尔埃博拉病毒（ZEBOV）感染，现在是最先进的病毒性出血热模型。尽管它们的重要性得到公认并且有良好模型的可用性，但仍缺乏经过批准的治疗方法，部分原因是对发病机制的了解不完全。免疫功能障碍似乎是丝状病毒出血热的主要组成部分，其特征是 I 型干扰素 (IFN) 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，许多细节仍然不明确，并且缺乏克服免疫失调的策略。该计划提出了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的假设。它将检验这个假设并定义有助于发病机制的免疫学机制。这将通过三个高度集成的项目的努力来实现，每个项目都有一个不同的目标。项目 1 将定义 IFN-拮抗剂-宿主因子相互作用的结构/生化基础，并识别相互作用突变的丢失。使用高效的慢病毒表达系统，影响将定义干扰素拮抗剂对 DC 成熟和功能的表达。最后，通过使用相互作用突变体缺失和基因表达敲低方法，将确定 IFN 拮抗剂对特定 DC 途径的影响。项目 2 将提出以下假设：EBOV 和 MARV 感染诱导的 DC 成熟破坏将导致 T 细胞活化受损和 T 细胞功能异常/缺失，并且丝状病毒 IFN 拮抗剂蛋白的机制对这些结果做出了关键贡献。项目3将表征感染过程中树突状细胞和淋巴细胞的表型和功能状态，测试这些群体是否因丝状病毒感染而失调，并确定IFN拮抗剂功能对体内免疫失调的贡献。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。他们的成功完成将为人们对导致病毒性出血热的免疫机制提供前所未有的见解。