Pulmonary Responses to Bacillus anthracis

对炭疽杆菌的肺部反应

基本信息

批准号：
7477194
负责人：
Mary Fisher Lipscomb
金额：
$ 21.62万
依托单位：
UNIVERSITY OF NEW MEXICO
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7477194
关键词：
Address Aerosols Alveolar Macrophages Animals Anthrax disease Antibodies Bacillus anthracis Bacillus anthracis spore Blood Circulation Breathing C5 Deficiency Classification Complement Complement component C5 Data Deposition Depth Development Disease Dose Early Diagnosis Edema Event Functional disorder Genes Genetic Germination Heating Host resistance Hour Human Immune response In Vitro Inbred BALB C Mice Inbred Mouse Infection Inflammatory Integration Host Factors Knowledge Lethal Dose 50 Lung Lymphoid Tissue Macaca fascicularis Modeling Monkeys Mus Numbers Organism Passive Immunization Pathogenesis Phagocytes Phenotype Plasmids Play Predisposition Purpose Relative (related person)Reproduction spores Resistance Risk Role Route Serum Signal Transduction Site Spleen Staging Standards of Weights and Measures Systemic infection Texas Therapeutic Toxin Universities Vaccination Vaccine Therapy Vaccines Variant Virulence Virulence Factors Virulent aerosolized anthrax lethal factor capsule congenic edema factor immunopathology killings lymph nodes macrophage mutant pathogen permissiveness reconstitution response subcutaneous uptake vaccination strategy

项目摘要

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，因为孢子的产生形式很容易雾化，吸入肺部脆弱的空腔深处，导致毁灭性的疾病——吸入性炭疽。我们对吸入孢子后肺部发生的基本免疫病理学的了解非常少。了解肺部如何对吸入的孢子做出反应，以及在萌发和传播过程中发生的炎症事件，以及毒力因子在从肺部逃逸、病原体存活和传播后对宿主造成损害方面发挥作用的知识，这些都是发育的先决条件有效的治疗和疫苗接种策略。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，小鼠和食蟹猴宿主在肺部炭疽芽孢杆菌孢子沉积后对系统性传播的许可程度是由生物体在肺部和区域淋巴组织中表达荚膜的能力决定的。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。具体来说，我们将：目标 1. 使用炭疽芽孢杆菌毒力菌株 UT500 和不能表达致死因子 (LF) 的 UT500 缺失突变体，评估重要的炭疽芽孢杆菌毒力因子在小鼠肺部感染中的作用，水肿因子 (EF)、LF+EF 或胶囊。然后，我们将通过将五种菌株中每一种的营养形式直接接种到血液中来比较这些毒力因子在全身感染中的作用。目标 2. 确定肺泡巨噬细胞和补体在小鼠早期肺部防御和剧毒炭疽杆菌传播中的作用，并评估荚膜和毒素抗体的保护作用。目标 3. 通过比较强毒力 UT500 和 LF、EF、LF+EF 和荚膜缺失突变体的肺部感染，评估重要的炭疽芽孢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五种菌株的营养体形式引起的全身感染中的作用。