Pulmonary Responses to Bacillus anthracis

炭疽芽孢杆菌可能是潜在的生物武器中最致命的，因为孢子可以以一种很容易被雾化的形式产生，然后吸入到肺部脆弱的空气深处，导致毁灭性的疾病--吸入性炭疽病。我们对孢子吸入后在肺部发生的基本免疫病理学的了解令人难以置信地差。了解肺部对吸入孢子的反应以及随后在萌发和传播过程中发生的炎症事件，以及哪些毒力因子在逃逸肺部、病原体存活和传播后对宿主的损害方面发挥作用，这些都是制定有效的治疗和疫苗接种策略的先决条件。此外，我们需要了解寄主的反应，这些反应负责增强寄主对 炭疽杆菌。我们的第一个假设是，小鼠和食蟹猴对肺部炭疽杆菌孢子沉积后全身传播的容许性取决于机体在肺部和区域淋巴组织中表达包膜的能力。我们的第二个假设是，肺巨噬细胞功能障碍和C5缺乏使宿主死于肺部炭疽感染的风险增加。具体地说，我们将：目的1.使用炭疽杆菌强毒株UT500和不表达致死因子(LF)的UT500缺失突变体，评估重要的炭疽杆菌毒力因子在小鼠肺部感染中的作用。 水肿因子(EF)，LFEF，或胶囊。然后，我们将通过将五种菌株的营养形态直接接种到血液中来比较这些毒力因子在系统性感染中的作用。目的2.确定肺泡巨噬细胞和补体在小鼠早期肺防御和炭疽强毒传播中的作用，并评价抗被膜抗体和毒素在保护中的作用。目的3.通过比较食蟹猴肺部感染与UT500毒力株、LF、EF、LF EF和衣壳缺失突变体的差异，评价重要的炭疽杆菌毒力因子在食蟹猴气溶胶感染中的作用。然后，我们将比较这些毒力因子在静脉接种诱导的系统性感染中所起的作用，并与五个菌株的营养形态进行比较。

Bacillus anthracis is perhaps the most deadly of potential bioweapons, because the spores can be produced in a form that can be readily aerosolized for inhalation deep into the vulnerable airspaces of the lung, causing the devastating disease, inhalation anthrax. Our understanding of the basic immunopathology that occurs in the lung after spore inhalation is incredibly poor. Knowledge of how the lung responds to inhaled spores and the inflammatory events that follow during germination and dissemination, along with which virulence factors play a role in escape from the lung, survival of the pathogen and damage to the host after dissemination are all prerequisites for development of effective therapeutic and vaccination strategies. Moreover, we need to understand the host responses that are responsible for enhancing host resistance to B. anthracis. Our first hypothesis is that murine and cynomolgus host permissiveness for systemic spread following pulmonary B. anthracis spore deposition is dictated by the ability of the organism to express capsule in the lungs and regional lymphoid tissues. Our second hypothesis is that lung macrophage dysfunction and C5 deficiency place the host at increased risk of dying from a pulmonary anthrax infection. Specifically we will: Aim 1. Assess the roles of important B. anthracis virulence factors in a pulmonary infection in mice, using a virulent B. anthracis strain, UT500, and deletion mutants of UT500 that fail to express lethal factor (LF), edema factor (EF), LF+EF, or capsule. We will then compare the role of these virulence factors in a systemic infection by inoculating the vegetative forms of each of the five strains directly into the bloodstream. Aim 2. Determine the roles for alveolar macrophages and complement in early pulmonary defenses and dissemination of virulent B. anthracis in mice, and assess the role of antibody to capsule and toxin in protection. Aim 3. Assess the roles of important B. anthracis virulence factors in an aerosol infection in cynomolgus monkeys by comparing lung infections with virulent UT500 and the LF, EF, LF+EF and capsule deletent mutants. We will then compare the role of these virulence factors in a systemic infection induced by IV inoculation with vegetative forms of each of the five strains.