Innate Immune Recognition of B. anthracis

描述(申请人提供)：2001年秋季人类炭疽病例引起的关注增加了我们更全面地了解在气雾剂暴露后宿主对炭疽芽孢杆菌感染的反应的需要。炭疽杆菌杀死宿主的机制尚不清楚，但暴露在气雾剂后的死亡率很高，即使使用了适当的抗生素。这表明炭疽杆菌可能能够逃避或颠覆感染后宿主反应的一个或多个元件。先天免疫系统通常提供对入侵病原体的第一识别和防御。宿主先天免疫细胞有一系列受体，用于感知、识别和启动对入侵病原体的反应；这些受体包括Toll样受体和细胞内NOD受体。本项目的总体目标是促进我们对炭疽杆菌宿主先天免疫反应的了解。随着对免疫识别途径和宿主免疫反应的更好了解，我们未来的目标将是识别免疫调节策略，以帮助防止在感染炭疽杆菌的宿主中观察到的典型的快速、猝死。这项提议的具体目标是识别识别炭疽芽胞和杆菌的宿主天然免疫受体。在特定的目标1中，我们将利用转染了选定受体的细胞系来确定生物体与宿主相互作用所激活的通路和受体。初步结果表明，Toll样受体2和MyD88依赖的通路参与了这一反应。在特定的目标2中，我们将使用小鼠气溶胶攻击模型来确定包括Toll样受体2在内的相关先天免疫受体在保护宿主免受吸入性炭疽感染中的作用。更全面地了解炭疽杆菌与宿主的相互作用将使我们能够评估炭疽杆菌疫苗和治疗的动物研究，为炭疽导向免疫疗法的发展提供基础，并提供适用于不同细菌病原体群体的重要基础信息。公共卫生相关性：炭疽芽孢杆菌是引起炭疽病的细菌病原体。吸入形式的炭疽通常会导致宿主猝死，尽管医护人员很早就认识到了这种感染，并及早使用了抗生素，正如2001年秋季的炭疽病例所见。这项研究的目标是确定炭疽芽孢杆菌如何与宿主的免疫系统相互作用，以便为医护人员制定帮助抗击感染的策略。

DESCRIPTION (provided by applicant): Concerns resulting from the human anthrax cases in the Fall of 2001 have increased our need for a more complete understanding of the host response to Bacillus anthracis infection following aerosol exposure. The mechanism by which B. anthracis kills the host remains unknown, but mortality is high following aerosol exposure even when appropriate antibiotics are administered. This suggests that B. anthracis may be capable of evading or subverting one or more elements of the host response following infection. The innate immune system typically provides the first recognition of and defense against invading pathogens. Host innate immune cells have a repertoire of receptors for sensing, recognizing, and initiating responses to invading pathogens; these receptors include Toll-like receptors and intracellular NOD receptors. The overall goal of this project is to advance our understanding of the host innate immune response to B. anthracis. With a better understanding of the immune recognition pathways and host immune response, our future goal will be to identify immunomodulatory strategies to help prevent the rapid, sudden death typically observed in a host infected with B. anthracis. The specific goals of this proposal are to identify those host innate immune receptors that recognize B. anthracis spores and bacilli. In Specific Aim 1, we will determine the pathways and receptors activated by the interaction of the organism with the host using cell lines transfected with selected receptors. Preliminary results implicate Toll-like receptor 2 and MyD88-dependent pathways in this response. In Specific Aim 2, we will determine the contribution of the relevant innate immune receptors including Toll-like receptor 2 to protection of the host from inhalational anthrax infection using a mouse aerosol challenge model. A more complete understanding of the interaction of B. anthracis with the host will allow us to evaluate animal-based studies of B. anthracis vaccines and therapeutics, provide a foundation for the development of anthrax-directed immunotherapeutics, and provide important fundamental information applicable to a diverse group of bacterial pathogens. PUBLIC HEALTH RELEVANCE: Bacillus anthracis is the bacterial pathogen that causes anthrax. The inhaled form of anthrax typically results in sudden death of the host in spite of early recognition of the infection by healthcare workers and early use of antibiotics, as was seen with the anthrax cases in the Fall of 2001. The goal of this research is to determine how Bacillus anthracis interacts with the host's immune system in order to devise strategies for healthcare workers to help fight the infection.