Bacillus Anthracis Spore -Host Interactions

炭疽芽孢杆菌孢子-宿主相互作用

• 批准号: 6832745
• 负责人: John Franklin Kearney
• 金额: $ 35.35万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6832745
• 关键词: Bacillus anthracis; anthrax; antibacterial antibody; bacteria infection mechanism; bioterrorism /chemical warfare; cell type; flow cytometry; host organism interaction; humoral immunity; immunization; laboratory mouse; microorganism immunology; spores; virulence

The use of Bacillus anthracis as a bioweapon depends on dispersal of its spores in the environment, entrance into the body, spore uptake by the human host cells, germination of the spores in the host, and the pathological consequences of the host response to the toxins elaborated by the vegetative cells within the host. Very little is known of the mechanisms of spore entry into the host, including targeted cell types at the surface of airways, digestive tract, and skin, and their subsequent initial encounter with cellular and humoral elements of the innate and adaptive immune response. An understanding of these host-spore interactions and the very early events that occur as the spores initiate the germination process will likely permit the development of an interventional vaccine or drug strategy that would act prior to the germination of spores and outgrowth of the vegetative form within the host and thus prevent development of Anthrax. We will identify mouse cell types and pathways involved in initial B. anthracis spore contact, and transport after binding to antigen processing cells following airway, intestinal or skin application. These goals will be achieved by a combination of flow cytometric analysis and analysis of tissue sections of skin, lung, and gut tissues. We will determine sites of residual spore retention and whether they induce chronic spore-specific immune responses that can be measured as an indicator of the spore load. If we can induce passive protective immunity with antibodies, we will attempt to elicit similar vaccine-induced immune responses and test the effects of these in long-term memory responses and determine the intracellular fate of spores if they are opsonized with different monoclonal antibodies. We will determine the basis for the sporicidal or germination inhibitory activity of antibodies. We will analyze such activity with classic bacteriological techniques as well as morphological studies. By identifying the spore-associated target molecules of these antibodies, we will be able to identify potential mechanisms to rapidly inactivate spores prior to establishment of infectious loci and vegetative cell outgrowth resulting in death from toxemia and septicemia. Therapeutic strategies of this nature would be a major supplement to the current PA-based vaccines as well as to the current recommended antibiotic regimens and in the case ofmultidrug-resistant B. anthracis strains engineered to produce additional toxins.

炭疽杆菌作为生物武器的使用取决于其孢子在环境中的传播、进入人体、孢子被人体宿主细胞摄取、孢子在宿主中的萌发以及宿主对宿主内营养细胞产生的毒素的反应的病理后果。孢子进入宿主的机制知之甚少，包括气道，消化道和皮肤表面的靶细胞类型，以及它们随后与先天免疫系统的细胞和体液成分的最初相遇。 和适应性免疫反应。了解这些宿主-孢子相互作用和孢子启动萌发过程时发生的非常早期的事件，将可能允许开发干预性疫苗或药物策略，其将在孢子萌发和宿主内营养体生长之前起作用，从而防止炭疽的发展。我们将确定参与初始B的小鼠细胞类型和途径。炭疽孢子接触，并在与抗原加工细胞结合后转运， 皮肤应用。这些目标将通过流式细胞术分析和皮肤、肺和肠组织的组织切片分析的组合来实现。我们将确定残留孢子滞留的部位，以及它们是否诱导慢性孢子特异性免疫反应，这些免疫反应可以作为孢子负荷的指标进行测量。如果我们可以用抗体诱导被动保护性免疫，我们将尝试引发类似的疫苗诱导的免疫应答，并测试这些免疫应答在长期记忆应答中的作用，并确定孢子在用不同单克隆抗体调理后的细胞内命运。我们将确定抗体杀孢子或抑制萌发活性的基础。我们将用经典的细菌学技术和形态学研究来分析这种活性。通过鉴定这些抗体的孢子相关靶分子，我们将能够鉴定在建立感染位点和营养体之前快速消灭孢子的潜在机制。 细胞生长导致死于毒血症和败血症。这种性质的治疗策略将是目前基于PA的疫苗以及目前推荐的抗生素方案的主要补充，并且在多药耐药B的情况下。炭疽菌菌株被改造以产生额外的毒素。