Early Host Immune Response in Protection Against Filovirus Infection

预防丝状病毒感染的早期宿主免疫反应

• 批准号: 8277871
• 负责人: Elke C Muhlberger
• 金额: $ 66.47万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-15 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8277871
• 关键词: Affect; Animal Model; Antibody Formation; Apoptosis; Attenuated; Biological Models; Cell Line; Cells; Clinical; Data; Dendritic Cells; Disease; Disease Outcome; Event; Exhibits; Exposure to; Failure; Family; Filovirus; Goals; Human; Immune; Immune response; Immune system; Immunity; Impairment; In Vitro; Individual; Infection; Infection Control; Inflammatory Response; Instruction; Lead; Ligands; Light; Lymphopenia; Mediating; Modeling; Mus; Pathogenesis; Pathogenicity; Pathway interactions; Principal Investigator; Production; Proteome; Receptor Activation; Receptor Signaling; Role; Signal Pathway; Site; Staging; Sudan; Survivors; Therapeutic Intervention; Toll-Like Receptor Pathway; Toll-like receptors; Vaccination; Vaccines; Vesicular stomatitis Indiana virus; Viral; Virus; Virus Diseases; Work; adaptive immunity; base; cell type; chemokine; cytokine; design; hemorrhagic fever virus; in vivo; macrophage; member; monocyte; nonhuman primate; research study; response

The members of the filovirus family, Ebola (EBOV) and Marburg (MARV) viruses, cause a severe hemorrhagic disease in infected humans and non-human primates with high fatality rates. Infected individuals who go on to succumb to EBOV exhibit disregulated immune responses which appears to result from several factors, including viral mediated impairment and disregulation of innate immune responses and subsequent failure to develop protective adaptive immunity. Studies of both human survivors and in animal models of EBOV disease suggest that a well-regulated cytokine response early in the course of the infection may be crucial to the outcome of the disease. Understanding the earliest events that occur in the interaction of the virus with cells of the host immune systems should shed light on the important determinants that influence the ability of a host to control the infection. The important early events are likely to center around monocytes, macrophages, and dendritic cells (DCs). These cells not only orchestrate innate and adaptive immune responses but are also the initial targets of viral infection. However, the available data on how these cells respond to EBOV infection is fragmentary and often contradictory. Therefore, developing a conceptual framework to understand how EBOV affects early innate responses remains challenging. This U01 proposal brings together the expertise to carefully dissect the early events of EBOV infection and pathogenesis in vitro and in vivo. The main objectives of this proposal are to: identify key events that lead to disregulated immunity in fatal Ebola disease, identify correlates of protection in survivors of EBOV infection and identify potential targets for therapeutic intervention both early in the host innate immune response, and later when uncontrolled inflammatory responses ensue. The aims are to 1) characterize the profiles of early cytokine and chemokine expression in EBOV infection, and compare how they differ to highly pathogenic less pathogenic EBOV; 2) determine if Toll-like receptors (TLRs) are activated by EBOV, and/or if EBOV infection individually or globally inhibits TLR activation in innate cells; 3) characterize the early cytokine responses in vivo, determine the role of TLRs and TLR signaling pathways on the pathogenesis of EBOV in vivo, and the role of alarmins in the "cytokine storm" that is a hall-mark of the late stages of EBOV infection; and 4) dissect the differences in early innate immune responses in a non-human primate model of EBOV disease upon infection by different EBOV species. The ultimate goal of this work is to identify new targets for therapeutic intervention into EBOV hemorrhagic disease. RELEVANCE (See instructions): The overall goals of the experiments outlined in the application are relevant to the NIAID's goals of understanding immune mechanisms of virus control, including how viruses and cells of the host innate immune system interact. The experiments are designed to identify new potential target for therapeutic interventions in hemorrhagic fever virus infections.

Filevirus家族，埃博拉（EBOV）和马尔堡（Marv）病毒的成员引起了严重的 感染人类和致命率高的非人类灵长类动物的出血性疾病。已感染 继续屈服于EBOV的个人表现出无视的免疫反应，这似乎是导致的 来自几个因素，包括病毒介导的损害和疏离先天免疫反应 并随后未能发展保护性适应性免疫。研究人类幸存者和 EBOV疾病的动物模型表明，在此期初，细胞因子反应良好 感染可能对疾病的结果至关重要。了解最早发生的事件 病毒与宿主免疫系统细胞的相互作用应阐明重要 影响宿主控制感染能力的决定因素。重要的早期事件可能是 围绕单核细胞，巨噬细胞和树突状细胞（DCS）中心。这些细胞不仅编排 先天和适应性免疫反应，但也是病毒感染的初始靶标。但是， 有关这些细胞如何对EBOV感染反应的可用数据是零散的，并且通常是矛盾的。 因此，开发一个概念框架以了解EBOV如何影响早期的先天反应 仍然具有挑战性。该U01提案汇集了专业知识，以仔细剖析 EBOV在体外和体内感染和发病机理。该提案的主要目标是：确定 导致致命埃博拉病毒免疫力无调的关键事件，确定保护的相关性 EBOV感染的幸存者并确定宿主早期的治疗干预措施的潜在靶标 先天免疫反应，后来随后发生不受控制的炎症反应。目的是1） 表征EBOV感染中早期细胞因子和趋化因子表达的特征，并比较如何 它们与高致病性的较少致病性EBOV不同。 2）确定电话样受体（TLR）是否为 由EBOV激活，以及/或如果EBOV感染单独或全局抑制先天细胞中的TLR激活； 3） 表征体内细胞因子的早期反应，确定TLR和TLR信号通路的作用 关于EBOV在体内的发病机理，以及警报在“细胞因子风暴”中的作用，这是 EBOV感染的晚期； 4）剖析早期先天免疫反应的差异 不同EBOV物种感染EBOV疾病的非人类灵长类动物模型。最终目标 这项工作是确定对EBOV出血疾病的治疗干预的新靶标。 相关性（请参阅说明）： 应用程序中概述的实验的总体目标与NIAID的目标有关 了解病毒控制的免疫机制，包括宿主先天的病毒和细胞 免疫系统相互作用。实验旨在确定治疗的新潜在靶标 出血热病毒感染的干预措施。