Protective Effects of Anti-BclA Antibodies in Bacillus anthracis Infection

抗 BclA 抗体对炭疽杆菌感染的保护作用

• 批准号: 8261444
• 负责人: Juan B Rodriguez Barrantes
• 金额: $ 3.41万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8261444
• 关键词: A/J Mouse; Active Immunization; Acute; Anthrax Attack; Anthrax disease; Antibiotic Therapy; Antibiotics; Antibodies; Antigens; Bacillus (bacterium); Bacillus anthracis; Bacillus anthracis spore; Bacteria; Binding; Cell membrane; Cells; Cessation of life; Collagen; Complex; Cutaneous; Development; Disease; Elements; Endemic Diseases; Engineering; Fc Receptor; Germination; Goals; Human; Immune; Immune response; Infection; Intervention; Intestines; Knowledge; Laboratories; Longitudinal Studies; Military Personnel; Monoclonal Antibodies; Mus; Nature; Organism; Outcome; Pathogenesis; Phagocytosis; Pharmaceutical Preparations; Play; Predisposition; Prevention; Production; Proteins; Regimen; Reproduction spores; Resistance; Role; Septic Toxemia; Septicemia; Site; Staging; Supportive care; Surface; Terrorism; Testing; Therapeutic; Toxin; United States; Vaccination; Vaccines; Work; base; cell type; in vivo; interest; killings; novel strategies; novel therapeutics; prevent; protective effect; public health relevance; receptor; uptake

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.

描述（由申请人提供）：抗BclA抗体对炭疽杆菌感染的保护作用2001年炭疽杆菌作为生物武器的使用凸显了了解这种普遍存在的细菌发病机制的重要性。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。这包括气道中目标细胞类型的性质以及随后孢子与先天性和适应性免疫反应的细胞和体液成分的初始接触。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介入疫苗或药物策略，这些疫苗或药物策略将在孢子在宿主体内萌发之前发挥作用，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，因为它们对通常非致病性的 Sterne 菌株具有天然敏感性。这限制了目前在 C57BL/6 背景上可用的转基因小鼠的使用。为了进行我们的研究，我们使用了一种新策略，其中我们利用 C57BL6 C5-/- 小鼠，我们已证明该小鼠以类似于 A/J 小鼠的方式对 Sterne 菌株敏感。这使得可以使用更多样的转基因小鼠来进行炭疽研究。我们还开发了针对 BclA 的特异性单克隆抗体，BclA 是炭疽芽孢杆菌外孢子的主要成分。这些高度特异性的抗体已证明对气管内感染炭疽芽孢杆菌的小鼠具有体内保护作用。我们将建立这些单克隆抗体的保护机制，其可以通过调理作用或直接杀伤发挥作用。我们将确定孢子外膜-抗体 Fc 受体相互作用在抵御孢子挑战方面的作用。有了这些知识，我们将能够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确定快速灭活孢子的潜在机制。这种性质的治疗策略将是对当前基于 PA 的疫苗以及当前推荐的抗生素治疗方案的主要补充，对于经过改造以产生额外毒素的多重抗性炭疽芽孢杆菌菌株而言。 公共卫生相关性：利用炭疽杆菌孢子传播作为恐怖主义媒介对于文职和军事人员来说仍然是一个重要问题。外孢子层是该生物体孢子阶段的最外层，是孢子与宿主细胞的第一个接触点。通过定义抗孢子抗体保护的机制和宿主细胞表面受体的作用，我们也许能够开发干预策略来诱导免疫保护或灭活或破坏孢子的药物，从而防止细菌发育、毒素的产生和死亡。