Pulmonary Responses to Bacillus anthracis

对炭疽杆菌的肺部反应

• 批准号: 6857532
• 负责人: Mary Fisher Lipscomb
• 金额: $ 23.12万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6857532
• 关键词: Bacillus anthracis; Macaca fascicularis; alveolar macrophages; anthrax; antibacterial antibody; bacteria infection mechanism; bactericidal immunity; bioterrorism /chemical warfare; complement; disease /disorder model; host organism interaction; laboratory mouse; respiratory infections; virulence

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.

炭疽杆菌可能是最致命的潜在生物武器，因为孢子可以以一种容易雾化的形式产生，吸入肺部脆弱的空气空间深处，导致毁灭性的疾病，吸入性炭疽病。我们对吸入孢子后肺部发生的基本免疫病理学的理解非常差。了解肺如何对吸入的孢子作出反应，以及在萌发和传播过程中随后发生的炎症事件，沿着毒力因子在从肺逃逸、病原体存活和传播后对宿主的损害中发挥作用，这些都是开发有效治疗和疫苗接种策略的先决条件。此外，我们需要了解负责增强宿主抵抗力的宿主反应， B。炭疽病我们的第一个假设是，小鼠和食蟹猴宿主对肺B后的全身传播具有宽容性。炭疽孢子沉积取决于生物体在肺和局部淋巴组织中表达荚膜的能力。我们的第二个假设是肺巨噬细胞功能障碍和C5缺乏使宿主死于肺炭疽感染的风险增加。具体而言，我们将：目标1。评估重要B的角色。炭疽菌毒力因子在小鼠肺部感染中的作用，使用毒性B。炭疽菌菌株UT500和不能表达致死因子（LF）的UT500缺失突变体， 水肿因子（EF）、LF+EF或胶囊。然后，我们将比较这些毒力因子在全身感染中的作用，方法是将五种菌株的营养体直接注入血液。目标2.确定肺泡巨噬细胞和补体在强毒B早期肺防御和传播中的作用。炭疽菌囊膜抗体和炭疽毒素抗体的保护作用。目标3.评估重要B的角色。通过比较强毒UT 500和LF、EF、LF+EF和荚膜缺失突变体的肺感染，研究了食蟹猴气溶胶感染中炭疽毒力因子的变化。然后，我们将比较这些毒力因子在静脉接种五种菌株的营养体诱导的全身感染中的作用。