Regulation of the Innate Immune Response to B Anthracis

对炭疽杆菌先天免疫反应的调节

• 批准号: 6803897
• 负责人: GARY M BOKOCH
• 金额: $ 223.3万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-15 至 2008-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6803897
• 关键词: Bacillus anthracis; anthrax toxin; bactericidal immunity; biotechnology; clinical research

DESCRIPTION (provided by applicant): The current threat of anthrax as an agent of biowarfare makes an understanding of the mechanisms used by anthrax toxins to suppress the innate immune response during the infectious process an important challenge for biomedical research. Much of what is currently known about the pathogenesis of anthrax infection derives from studies conducted in animals, primarily mice, where clear differences from human responses are evident. Since little is known about the molecular basis for the pathogenesis of Bacillus anthracis and its toxins in humans, we propose in this Program Project to investigate in molecular detail how Bacillus anthracis interacts with human host defense mechanisms. The individual projects in this Program will probe the molecular targets and biochemical consequences of B. anthracis action in airway epithelial cells, macrophages and neutrophils, and will define genetic elements that determine susceptibility to anthrax infection and progression. Each project will, however, relate to the central theme of investigating innate host defense mechanisms and share commonality in the molecular mechanisms to be studied. Project 1 will search for genetic elements that modulate the organismal response to lethal toxin using a genetic screen in mice. Project 2 will investigate the influence of B. anthracis and its toxins on human alveolar macrophage phagolysosome function and on their ability to generate inflammatory mediators. Project 3 will examine the responses of human airway epithelial cells to B. anthracis and its toxins, including the involvement of Toll receptors, Rho GTPases, and Nox's in cellular responses. Project 4 will elucidate the molecular basis for the action of anthrax toxins to suppress the chemotactic and oxidative responses of human neutrophils and macrophages, and will investigate the basis for differences in toxin action between these types of leukocyte. Project 5 will assess human Nox proteins as components of host defense and evaluate how variations in the genetic background of humans may influence their responsiveness to B. anthracis infection. Two cores are proposed in support of this Program: an Administrative Core and a Microbiological and Biological Reagents Core. This Program Project will leverage the diverse areas of expertise, resources, and experimental approaches of its members into a focused, highly interactive investigation of human innate immune responsiveness during infection by anthrax. Together these projects will characterize key molecular targets and mechanisms that contribute to the virulence of anthrax. Efforts to identify the process leading to innate immune suppression by anthrax will provide a new molecular basis for disease intervention.

描述（由申请人提供）： 当前炭疽作为生物战剂的威胁使得了解炭疽毒素在感染过程中抑制先天免疫反应的机制成为生物医学研究的重要挑战。目前对炭疽感染发病机制的了解大部分来自于对动物（主要是小鼠）进行的研究，这些动物的反应与人类的反应存在明显差异。由于人们对炭疽杆菌及其毒素在人类发病机制的分子基础知之甚少，我们建议在本计划项目中详细研究炭疽杆菌如何与人类宿主防御机制相互作用。 该计划中的各个项目将探讨炭疽杆菌在气道上皮细胞、巨噬细胞和中性粒细胞中作用的分子靶标和生化后果，并将确定决定炭疽感染和进展易感性的遗传元件。然而，每个项目都将涉及研究先天宿主防御机制的中心主题，并在要研究的分子机制中具有共性。项目 1 将利用小鼠基因筛选来寻找调节机体对致命毒素反应的遗传元件。项目2将研究炭疽芽孢杆菌及其毒素对人类肺泡巨噬细胞吞噬溶酶体功能及其产生炎症介质的能力的影响。项目 3 将检查人类气道上皮细胞对炭疽杆菌及其毒素的反应，包括 Toll 受体、Rho GTPases 和 Nox's 在细胞反应中的参与。项目4将阐明炭疽毒素抑制人类中性粒细胞和巨噬细胞趋化和氧化反应的分子基础，并将研究这些类型白细胞之间毒素作用差异的基础。项目 5 将评估人类 Nox 蛋白作为宿主防御的组成部分，并评估人类遗传背景的变化如何影响他们对炭疽杆菌感染的反应。建议设立两个核心来支持该计划：行政核心和微生物和生物试剂核心。 该计划项目将利用其成员的不同领域的专业知识、资源和实验方法，对炭疽感染期间的人类先天免疫反应进行重点、高度互动的研究。这些项目将共同描述导致炭疽毒力的关键分子靶点和机制。确定炭疽导致先天免疫抑制的过程将为疾病干预提供新的分子基础。