Innate Immune Recognition of B. anthracis

炭疽芽孢杆菌的先天免疫识别

• 批准号: 7633403
• 负责人: MOLLY A HUGHES
• 金额: $ 18.94万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-09 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7633403
• 关键词: Aerosols; Animals; Anthrax disease; Antibiotics; Bacillus (bacterium); Bacillus anthracis; Bacillus anthracis spore; Breathing; Cell Line; Cells; Development; Elements; Encapsulated; Exposure to; Foundations; Future; Goals; Health Personnel; Human; Immune; Immune response; Immune system; Immunologic Receptors; Immunotherapeutic agent; In Vitro; Infection; Invaded; Knowledge; Life; Methods; Modeling; Mouse Strains; Mus; Organism; Pathway interactions; Reproduction spores; Research; Research Proposals; Serum; Sudden Death; TLR2 gene; TLR4 gene; Testing; Tissues; Toll-Like Receptor 2; Toll-like receptors; aerosolized; base; cytokine; falls; fighting; in vivo; killings; macrophage; mortality; pathogen; prevent; public health relevance; receptor; response; therapeutic vaccine

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.

描述（由申请人提供）：由于 2001 年秋季的人类炭疽病例引起的担忧，我们更加需要更全面地了解气溶胶暴露后宿主对炭疽杆菌感染的反应。炭疽杆菌杀死宿主的机制仍不清楚，但即使使用适当的抗生素，气溶胶暴露后死亡率也很高。这表明炭疽芽孢杆菌可能能够逃避或破坏感染后宿主反应的一种或多种要素。先天免疫系统通常首先识别并防御入侵的病原体。宿主先天免疫细胞具有一系列受体，用于感知、识别入侵病原体并启动反应；这些受体包括Toll样受体和细胞内NOD受体。该项目的总体目标是增进我们对宿主对炭疽杆菌的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确定免疫调节策略，以帮助预防通常在感染炭疽杆菌的宿主中观察到的快速、突然死亡。该提案的具体目标是确定那些识别炭疽芽孢杆菌孢子和杆菌的宿主先天免疫受体。在具体目标 1 中，我们将使用转染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途径和受体。初步结果表明 Toll 样受体 2 和 MyD88 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攻击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。对炭疽芽孢杆菌与宿主相互作用的更全面了解将使我们能够评估炭疽芽孢杆菌疫苗和治疗方法的动物研究，为炭疽定向免疫治疗的开发提供基础，并提供适用于炭疽芽孢杆菌疫苗和治疗方法的重要基础信息。一组不同的细菌病原体。公共卫生相关性：炭疽杆菌是引起炭疽的细菌病原体。尽管医护人员及早发现了感染并及早使用了抗生素，吸入形式的炭疽通常会导致宿主突然死亡，正如 2001 年秋季的炭疽病例所见。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帮助对抗感染的策略。