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: 8434951
• 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/8434951
• 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.

描述（由申请人提供）：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强调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、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。特别感兴趣的是孢子进入宿主的机制。这包括气道中靶细胞类型的性质以及随后的初始孢子与先天性和适应性免疫应答的细胞和体液成分的接触。了解这些孢子-宿主相互作用和对孢子的早期免疫反应将允许开发干预性疫苗或药物策略，其将在孢子在宿主内萌发之前起作用，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，因为它们对正常非致病性Sterne菌株具有天然易感性。这限制了目前在C57 BL/6背景下可用的遗传修饰小鼠的使用。为了进行我们的研究，我们使用了一种新的策略，其中我们利用C57 BL 6 C5-/-小鼠，我们已经证明，以类似于A/J小鼠的方式对Sterne菌株易感。这允许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的单克隆抗体，BclA是B的主要成分。炭疽病孢子外壁。这些高度特异性的抗体已经证明在用B进行肠道内感染的小鼠中具有体内保护作用。炭疽病我们将建立这些单克隆抗体的保护机制，其可能通过调理作用或直接杀伤起作用。我们将确定孢子外壁抗体Fc受体相互作用对孢子攻击的保护作用。有了这方面的知识，我们将能够确定潜在的机制，迅速消灭孢子之前，建立感染位点和营养细胞生长，导致死亡的毒血症和败血症。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，并且在多重耐药B的情况下。炭疽菌菌株被改造以产生额外的毒素。