Protective Effects of Anti-BclA Antibodies in Bacillus anthracis Infection

描述（由申请人提供）：抗bcla抗体在炭疽芽孢杆菌感染中的保护作用2001年炭疽芽孢杆菌作为生物武器的使用表明了理解这种普遍存在的细菌的发病机制的重要性。尚未完全阐明的机制包括人类宿主细胞的摄取，宿主中孢子的萌发以及宿主对宿主内营养细胞产生的毒素反应的病理后果。特别令人感兴趣的是孢子进入宿主的机制。这包括气道中目标细胞类型的性质以及随后的初始孢子与先天和适应性免疫反应的细胞和体液元素的接触。了解这些孢子与宿主的相互作用以及对孢子的早期免疫反应，将有助于开发一种介入性疫苗或药物策略，在孢子在宿主内发芽之前起作用，从而防止炭疽的发展。为了了解这些相互作用，大多数实验室使用A/J小鼠，因为它们对通常非致病性的斯特恩菌株天然易感性。这限制了目前在C57BL/6基因背景下转基因小鼠的使用。为了进行我们的研究，我们使用了一种新的策略，我们使用了C57BL6 C5-/-小鼠，我们已经证明这些小鼠对Sterne菌株的易感性与a /J小鼠相似。这使得使用更多样化的转基因小鼠小组进行炭疽研究成为可能。我们还开发了针对BclA的单克隆抗体，BclA是炭疽芽孢杆菌的主要成分。这些高度特异性的抗体在小鼠气管内感染炭疽芽孢杆菌中显示出体内保护作用。我们将建立这些单克隆抗体的保护机制，它们可能通过调理或直接杀伤发挥作用。我们将确定胞外孢子-抗体Fc受体相互作用对孢子攻击的保护作用。有了这些知识，我们将能够确定在感染位点建立和营养细胞生长导致毒血症和败血症死亡之前快速灭活孢子的潜在机制。这种性质的治疗策略将是目前基于pa的疫苗的主要补充，也是目前推荐的抗生素方案的主要补充，对于设计产生额外毒素的多重耐药炭疽杆菌菌株也是如此。

DESCRIPTION (provided by applicant): Protective Effects of anti-BclA Antibodies in Bacillus anthracis infection The use of Bacillus anthracis as a bioweapon in 2001 underlies the importance of understanding the mechanisms of pathogenesis of this ubiquitous bacterium. The mechanisms that have yet to be completely elucidated include 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. Of particular interest are the mechanisms of spore entry into the host. This includes the nature of targeted cell types in the airways and subsequent initial spore encounter with cellular and humoral elements of the innate and adaptive immune response. An understanding of these spore-host interactions and the early immune response to the spores will allow the development of an interventional vaccine or drug strategy that would act prior to the germination of spores within the host and thus prevent development of Anthrax. In order to understand these interactions, most laboratories use A/J mice due to their natural susceptibility to the normally non-pathogenic Sterne strain. This limits the use of genetically modified mice currently available on the C57BL/6 background. In order to conduct our studies, we use a novel strategy in which we utilize C57BL6 C5-/- mice that we have proved susceptible to the Sterne strain in a manner similar to A/J mice. This allows the use of a more diverse panel of genetically modified mice to conduct Anthrax studies. We have also developed monoclonal antibodies specific to BclA, a major component of the B. anthracis exosporium. These highly specific antibodies have demonstrated protective in vivo effects in mice intratracheally infected with B. anthracis. We will establish the mechanisms of protection of these monoclonal antibodies, which may act via opsonization or direct killing. We will determine the role of exosporium-antibody Fc receptor interactions on protection against spore challenges. With this knowledge 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 of multi- resistant B. anthracis strains engineered to produce additional toxins. PUBLIC HEALTH RELEVANCE: The use of Bacillus anthracis spore dispersal as an agent of terrorism remains an important issue to both civilian and military personnel. The exosporium, being the outermost layer of the spore stage of this organism, is the first point of contact of spores with host cells. By defining the mechanisms of anti-spore antibody protection and the role surface receptors on host cells play, we may be able to develop interventional strategies to induce immune protection or drugs that will inactivate or destroy spores, thus preventing bacterial development, the elaboration of toxins, and death.