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

描述（由申请人提供）：线状病毒，埃博拉病毒（ebov）和马尔堡病毒（marv）是A类优先病原体，可引起人类高致命性出血热，致死率接近90%（20）。具有良好特征的非人类灵长类丝状病毒感染模型，特别是扎伊尔埃博拉病毒（ZEBOV），是目前发展最好的病毒性出血热模型。尽管它们的重要性和良好模型的可用性得到了公认，但由于对发病机制的不完全理解，目前尚缺乏经批准的治疗方法。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，并且缺乏克服失调免疫的策略。该计划解决丝状病毒ifn拮抗剂蛋白在丝状病毒感染的免疫失调特征中起核心作用的假设。它将检验这个假设并定义

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.