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.

丝状病毒家族的成员埃博拉(EBOV)和马尔堡(Marv)病毒会导致严重的 感染人类和非人类灵长类动物中的出血性疾病，病死率很高。受感染的 后来死于EBOV的人表现出免疫反应失调，这似乎会导致 从几个因素，包括病毒介导的损害和先天免疫反应的失调 以及随后未能形成保护性适应性免疫。对人类幸存者和 EBOV疾病的动物模型表明，在EBOV疾病过程的早期，调节良好的细胞因子反应 感染可能对疾病的结局至关重要。了解最早发生在 病毒与宿主免疫系统细胞的相互作用应该揭示出重要的 影响宿主控制感染能力的决定因素。重要的早期事件很可能是 以单核细胞、巨噬细胞和树突状细胞(DC)为中心。这些细胞不仅协调 先天和获得性免疫反应，但也是病毒感染的最初目标。然而， 关于这些细胞如何应对EBOV感染的现有数据并不完整，而且往往相互矛盾。 因此，开发一个概念框架来理解EBOV如何影响早期先天反应 仍然具有挑战性。这份U01提案汇集了专业知识，仔细剖析了 体内外EBOV感染及其致病机制。这项提案的主要目标是：确定 导致致命埃博拉疾病免疫失调的关键事件，确定保护的相关因素 EBOV感染的幸存者并在宿主早期确定潜在的治疗干预目标 先天免疫反应，后来当失控的炎症反应接踵而至。目标是1) 描述早期细胞因子和趋化因子在EBOV感染中的表达情况，并比较 它们不同于高致病性、低致病性的EBOV；2)确定Toll样受体(TLRs)是否 被EBOV激活，和/或EBOV单独或整体感染抑制天然细胞中TLR的激活；3) 体内早期细胞因子反应的特征，确定TLRs和TLR信号通路的作用 论EBOV的体内致病机制及警素在以EBOV为标志的细胞因子风暴中的作用 EBOV感染的晚期；4)剖析了早期先天免疫反应的差异。 不同EBOV感染的非人灵长类动物模型。的最终目标是 这项工作是为了确定EBOV出血性疾病治疗干预的新靶点。 相关性(请参阅说明)： 申请中概述的实验的总体目标与NIAID的目标相关 了解病毒控制的免疫机制，包括病毒和宿主细胞如何与生俱来 免疫系统相互作用。这些实验旨在确定新的潜在治疗靶点。 出血热病毒感染的干预措施。