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: 8099009
• 负责人: Elke C Muhlberger
• 金额: $ 64.72万
• 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/8099009
• 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 response; Immune system; Immunity; Impairment; In Vitro; Individual; Infection; Infection Control; Inflammatory Response; 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; in vivo; macrophage; member; monocyte; nonhuman primate; response

DESCRIPTION (provided by applicant): 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 application 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 application 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.

描述（由申请人提供）：丝状病毒家族的成员埃博拉病毒（EBOV）和马尔堡病毒（MARV）会在受感染的人类和非人类灵长类动物中引起严重的出血性疾病，死亡率很高。继续死于埃博拉病毒的感染者表现出免疫反应失调，这似乎是由多种因素造成的，包括病毒介导的损伤和先天免疫反应失调以及随后未能发展出保护性适应性免疫。对人类幸存者和埃博拉病毒疾病动物模型的研究表明，感染早期良好调节的细胞因子反应可能对该疾病的结果至关重要。了解病毒与宿主免疫系统细胞相互作用中发生的最早事件应该有助于揭示影响宿主控制感染能力的重要决定因素。重要的早期事件可能以单核细胞、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，而且还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理解埃博拉病毒如何影响早期先天反应仍然具有挑战性。该 U01 应用汇集了专业知识，可以仔细剖析 EBOV 感染的早期事件以及体外和体内的发病机制。该应用的主要目标是：确定导致致命埃博拉疾病免疫失调的关键事件，确定 EBOV 感染幸存者的保护相关性，并确定宿主先天免疫反应早期和后期治疗干预的潜在目标。随之而来的是不受控制的炎症反应。目的是 1) 描述 EBOV 感染中早期细胞因子和趋化因子表达的特征，并比较它们与高致病性和低致病性 EBOV 的差异； 2) 确定Toll样受体(TLR)是否被EBOV激活，和/或EBOV感染是否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信号通路在体内EBOV发病机制中的作用，以及警报素在作为EBOV晚期标志的“细胞因子风暴”中的作用感染; 4) 剖析非人类灵长类动物埃博拉病毒疾病模型在感染不同埃博拉病毒物种后早期先天免疫反应的差异。这项工作的最终目标是确定治疗干预 EBOV 出血性疾病的新靶点。