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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

基本信息

批准号：
8474594
负责人：
Elke C Muhlberger
金额：
$ 62.48万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-15 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8474594
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

项目摘要

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病毒 (EBOV) 和马尔堡病毒 (MARV) 会导致严重的受感染的人类和非人类灵长类动物的出血性疾病，死亡率很高。已感染继续死于埃博拉病毒的个体表现出失调的免疫反应，这似乎导致来自多种因素，包括病毒介导的损伤和先天免疫反应的失调以及随后未能发展出保护性适应性免疫。对人类幸存者和人类幸存者的研究埃博拉病毒疾病的动物模型表明，在疾病早期，细胞因子反应受到良好调节感染可能对该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该揭示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发生以单核细胞、巨噬细胞和树突状细胞 (DC) 为中心。这些细胞不仅协调先天性和适应性免疫反应也是病毒感染的最初目标。然而，关于这些细胞如何应对埃博拉病毒感染的现有数据是零散的，而且常常是矛盾的。因此，开发一个概念框架来了解埃博拉病毒如何影响早期先天反应仍然具有挑战性。这项 U01 提案汇集了专业知识，仔细剖析了 U01 的早期事件埃博拉病毒体外和体内感染和发病机制。该提案的主要目标是：导致致命埃博拉疾病免疫失调的关键事件，确定保护的相关性埃博拉病毒感染幸存者并确定宿主早期治疗干预的潜在目标先天免疫反应，以及随后发生不受控制的炎症反应。目标是 1) 描述 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、低致病性埃博拉病毒不同； 2) 确定Toll样受体(TLR)是否被 EBOV 激活，和/或 EBOV 感染单独或整体抑制先天细胞中的 TLR 激活； 3）表征体内早期细胞因子反应，确定 TLR 和 TLR 信号通路的作用埃博拉病毒体内发病机制的研究，以及警报素在“细胞因子风暴”中的作用，这是细胞因子风暴的标志埃博拉病毒感染的晚期阶段； 4）剖析早期先天免疫反应的差异不同 EBOV 物种感染后的 EBOV 疾病非人灵长类动物模型。最终目标是这项工作旨在确定治疗干预 EBOV 出血性疾病的新靶标。相关性（参见说明）：申请中概述的实验总体目标与 NIAID 的目标相关了解病毒控制的免疫机制，包括宿主的病毒和细胞如何先天免疫系统相互作用。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。