Early Host Immune Response in Protection Against Filovirus Infection

描述（由申请方提供）：丝状病毒家族成员埃博拉病毒（EBOV）和马尔堡病毒（MARV）在感染的人类和非人灵长类动物中引起严重出血性疾病，具有高致死率。继续屈服于EBOV的感染个体表现出失调的免疫应答，这似乎是由几种因素引起的，包括病毒介导的损伤和先天免疫应答失调以及随后未能发展保护性适应性免疫。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应答可能对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，应该有助于了解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）周围。这些细胞不仅协调先天性和适应性免疫反应，而且也是病毒感染的最初目标。然而，关于这些细胞如何响应EBOV感染的现有数据是不完整的，并且经常相互矛盾。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。U 01应用汇集了专业知识，以仔细剖析体外和体内EBOV感染和发病机制的早期事件。本申请的主要目的是：鉴定导致致命性埃博拉疾病中免疫失调的关键事件，鉴定EBOV感染幸存者中的保护相关性，并鉴定在宿主先天免疫应答早期和随后不受控制的炎症应答时进行治疗干预的潜在靶标。目的是1）表征EBOV感染中早期细胞因子和趋化因子表达的概况，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（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TLR的激活; 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alarmins在作为EBOV感染晚期标志的“细胞因子风暴”中的作用;和4）剖析EBOV疾病的非人灵长类动物模型中在被不同EBOV物种感染后早期先天免疫应答的差异。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。

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.