Early Host Immune Response in Protection Against Filovirus Infection

描述(申请人提供)：丝状病毒家族的成员，埃博拉(EBOV)和马尔堡(MARV)病毒，在受感染的人和非人类灵长类动物中引起一种严重的出血性疾病，死亡率很高。感染EBOV的人表现出免疫反应失控，这似乎是由几个因素引起的，包括病毒介导的天然免疫反应的损害和失控，以及随后未能形成保护性适应性免疫。对人类幸存者和EBOV疾病动物模型的研究表明，在感染过程早期调节良好的细胞因子反应可能对疾病的结局至关重要。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集中在单核细胞、巨噬细胞和树突状细胞(DC)。这些细胞不仅协调先天和获得性免疫反应，而且也是病毒感染的初始目标。然而，关于这些细胞如何应对EBOV感染的现有数据是零散的，而且往往是相互矛盾的。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是具有挑战性的。这个U01应用程序汇集了专业知识，仔细剖析了EBOV感染的早期事件和体外和体内的致病机制。该应用程序的主要目标是：识别导致致命埃博拉疾病免疫失调的关键事件，识别对EBOV感染幸存者的保护相关因素，并确定治疗干预的潜在靶点，包括宿主先天免疫反应早期和随后发生失控炎症反应时。本研究的目的是：1)研究EBOV感染早期细胞因子和趋化因子的表达谱，并比较它们与高致病性、低致病性EBOV的差异；2)确定Toll样受体(TLRs)是否被EBOV激活，和/或EBOV感染是否单独或整体抑制固有细胞中TLR的激活；3)表征体内早期细胞因子的反应，确定TLRs和TLR信号通路在EBOV体内发病机制中的作用，以及Almins在EBOV感染晚期的细胞因子风暴中的作用；4)分析不同EBOV感染的非人灵长类动物模型中早期先天免疫反应的差异。这项工作的最终目标是为EBOV出血性疾病的治疗干预确定新的靶点。

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.