Bacillus Anthracis Spore -Host Interactions

炭疽芽孢杆菌作为生物武器的使用取决于其孢子在环境中的扩散、进入人体、人类宿主细胞对孢子的摄取、孢子在宿主中的萌发以及宿主对宿主内营养细胞所阐述的毒素的反应的病理后果。人们对孢子进入宿主的机制知之甚少，包括呼吸道、消化道和皮肤表面的靶向细胞类型，以及它们随后与先天的细胞和体液成分的最初接触。 和适应性免疫反应。了解这些寄主-孢子的相互作用和孢子萌发过程中发生的非常早期的事件，将可能有助于开发一种介入性疫苗或药物策略，该策略将在孢子萌发和寄主内营养形态生长之前采取行动，从而防止炭疽病的发展。我们将确定小鼠的细胞类型和参与炭疽芽胞最初接触的途径，以及在与抗原处理细胞结合后经呼吸道、肠道或 皮肤应用程序。这些目标将通过结合流式细胞仪分析和皮肤、肺和肠道组织的组织切片分析来实现。我们将确定残留孢子滞留的位置，以及它们是否会引发可作为孢子载量指标的慢性孢子特异性免疫反应。如果我们能用抗体诱导被动保护性免疫，我们将尝试诱导类似的疫苗诱导的免疫反应，并测试这些反应在长期记忆反应中的效果，并确定如果孢子被不同的单抗调理，它们在细胞内的命运。我们将确定抗体的杀孢子活性或萌发抑制活性的基础。我们将用经典的细菌学技术以及形态研究来分析这种活性。通过识别这些抗体的孢子相关靶分子，我们将能够确定在感染点和营养体区建立之前快速灭活孢子的潜在机制。 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对目前以PA为基础的疫苗以及当前推荐的抗生素方案的主要补充，对于经过改造以产生额外毒素的多重耐药炭疽杆菌菌株而言。

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.