Protective Effects of Anti-BclA Antibodies in Bacillus anthracis Infection

描述(申请人提供)：抗BCLA抗体在炭疽杆菌感染中的保护作用2001年炭疽杆菌作为生物武器的使用突显了了解这种普遍存在的细菌的致病机理的重要性。尚未完全阐明的机制包括人类宿主细胞的摄取、宿主内孢子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。特别令人感兴趣的是孢子进入宿主的机制。这包括呼吸道中靶细胞类型的性质，以及随后与先天和获得性免疫反应的细胞和体液成分的初始孢子相遇。了解这些孢子-宿主相互作用和对孢子的早期免疫反应将有助于开发介入性疫苗或药物策略，该策略将在宿主内孢子萌发之前采取行动，从而防止炭疽病的发展。为了了解这些相互作用，大多数实验室使用A/J小鼠，因为它们对正常非致病的Sterne菌株具有天然的敏感性。这限制了目前在C57BL/6背景下可用的转基因小鼠的使用。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以类似于A/J小鼠的方式对Sterne菌株敏感。这使得可以使用更多样化的转基因小鼠小组来进行炭疽研究。我们还开发了针对BCLA的单抗，BCLA是炭疽杆菌外孢子菌的主要成分。这些高度特异的抗体对气管内感染炭疽杆菌的小鼠具有体内保护作用。我们将建立这些单抗的保护机制，这些单抗可能通过调理或直接杀伤发挥作用。我们将确定外孢子体-抗体Fc受体相互作用在保护孢子攻击方面的作用。有了这些知识，我们将能够确定在感染点和营养细胞生长之前迅速灭活孢子的潜在机制，从而导致毒血症和败血症死亡。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。

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.