Innate Immune Recognition of B. anthracis

描述（由申请人提供）：2001年秋季人类炭疽病例引起的关注增加了我们对更全面了解气溶胶暴露后宿主对炭疽杆菌感染的反应的需求。B.炭疽病是否能杀死宿主仍不清楚，但即使使用了适当的抗生素，接触气雾剂后的死亡率也很高。这表明B.炭疽菌可能能够逃避或破坏感染后宿主反应的一个或多个要素。先天免疫系统通常提供对入侵病原体的第一识别和防御。宿主先天免疫细胞具有用于感测、识别和启动对入侵病原体的反应的受体库;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宿主对B的先天免疫反应的理解。炭疽病随着对免疫识别途径和宿主免疫应答的更好理解，我们未来的目标将是确定免疫调节策略，以帮助预防通常在感染B的宿主中观察到的快速猝死。炭疽病这项提议的具体目标是鉴定那些识别B的宿主先天免疫受体。炭疽孢子和杆菌。在特定目标1中，我们将使用转染选定受体的细胞系确定生物体与宿主相互作用激活的途径和受体。初步结果表明Toll样受体2和MyD 88依赖性途径参与了这种反应。在具体目标2中，我们将使用小鼠气溶胶激发模型确定相关先天免疫受体（包括Toll样受体2）对保护宿主免受吸入性炭疽感染的贡献。对B的相互作用有了更完整的理解。炭疽菌与宿主的关系将使我们能够评估基于动物的B研究。炭疽疫苗和治疗剂，为炭疽导向的免疫治疗剂的开发提供了基础，并提供了适用于各种细菌病原体的重要基础信息。公共卫生相关性：炭疽杆菌是导致炭疽的细菌病原体。吸入形式的炭疽通常会导致宿主突然死亡，尽管医护人员很早就发现了感染并很早就使用了抗生素，正如2001年秋季的炭疽病例所示。这项研究的目的是确定炭疽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策略来帮助对抗感染。

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.