Bordetella cyclase toxin: effects on leukocytes and respiratory epithelial cells

博德特氏菌环化酶毒素：对白细胞和呼吸道上皮细胞的影响

• 批准号: 7846692
• 负责人: ERIK L HEWLETT
• 金额: $ 3.22万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-05 至 2011-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7846692
• 关键词: Address; Adenylate Cyclase; Adenylate Cyclase Toxin; Adherence; Adherent Culture; Affect; Animals; Bacteria; Bacterial Adhesins; Binding; Biological; Bordetella; Bordetella Virulence Factors; CD14 gene; Canis familiaris; Cell membrane; Cell physiology; Cells; Chemotaxis; Collection; Coughing; Cyclic AMP; Cyclic AMP Receptors; Cytotoxin; Data; Disease; Epithelial Cells; Epithelium; Evaluation; Generations; Hemagglutinin; Human; In Vitro; Individual; Infection; Integrins; Lead; Learning; Leukocytes; Lung diseases; MAP Kinase Gene; MAPK8 gene; Macrophage-1 Antigen; Mammals; Membrane; Modeling; Mutation; NF-kappa B; Nitric Oxide; Organism; Pathogenesis; Permeability; Pertussis; Pertussis Toxin; Phagocytosis; Phase; Phosphorylation; Preparation; Production; Research Personnel; Resistance; Respiratory System; Respiratory tract structure; Role; Signal Pathway; Signal Transduction; Signaling Protein; Structure; Structure of respiratory epithelium; Superoxides; Surface; TLR4 gene; Testing; Tissues; Toxin; Vesicle; Virulence Factors; Work; bactericide; cell type; chemokine; cytokine; cytotoxicity; killings; macrophage; monocyte; monolayer; mutant; neutrophil; novel; pertactin; prevent; programs; protein activation; protein kinase A kinase; receptor; receptor-mediated signaling; release of sequestered calcium ion into cytoplasm; research study; respiratory

DESCRIPTION (provided by applicant): Adenylate cyclase (AC) toxin is a novel virulence factor for several species of the genus Bordetella, including B. pertussis (whooping cough, pertussis in humans), B. parapertussis (different strains causing diseases in animals and humans) and B. bronchiseptica (kennel cough in dogs, and respiratory diseases in most mammals). Its major function has been considered to be the ability to translocate its AC domain across the cytoplasmic membrane of target cells and produce supraphysiologic quantities of cAMP. We have now demonstrated, however, that the ability of AC toxin to form transmembrane pores is also relevant to cytotoxicity for macrophages. Furthermore, simply binding of the toxin to CR3, a leukocyte integrin that can act as a receptor for AC toxin, can activate human neutrophils (PMN), independent of its cAMP production and pore formation. In this renewal proposal, we will develop these recent discoveries and focus on the mechanisms and target tissues through which AC toxin is indispensable to B. pertussis in the establishment of infection in the respiratory tract. We will use in vitro approaches with either purified toxin or bordetella organisms (both B. pertussis and B. bronchiseptica) to learn more about toxin composition, packaging, secretion and delivery (SA I), the effects of the toxin on the two prime candidate target tissues, leukocytes (SA II) and the respiratory epithelium (SA III), through its three functions (occupancy of integrin receptor, cAMP production and pore formation). Finally, in order to begin to relate the actions of AC toxin to those of other important virulence factors, we will evaluate other toxins (pertussis toxin, tracheal cytotoxin) and adhesins (filamentous hemagglutinin, pertactin) from B. pertussis, both individually and in conjunction with AC toxin, to understand better the possible interactions (enhancement, synergy, antagonism or no effect) of their effects in leukocytes and the respiratory epithelium (SA IV). The objective is to apply the information on AC toxin and on other bordetellae virulence factors, to a more focused study of how AC toxin contributes to infections and diseases caused by this genus.

描述（由申请方提供）：腺苷酸环化酶（AC）毒素是几种博德特氏菌属（包括B）的新型毒力因子。百日咳（百日咳，人百日咳），B.副百日咳（在动物和人类中引起疾病的不同菌株）和B。支气管炎（犬的犬舍咳嗽和大多数哺乳动物的呼吸道疾病）。其主要功能被认为是能够将其AC结构域跨靶细胞的细胞质膜移位并产生超生理量的cAMP。然而，我们现在已经证明AC毒素形成跨膜孔的能力也与巨噬细胞的细胞毒性相关。此外，毒素与CR3（一种可作为AC毒素受体的白细胞整联蛋白）的简单结合可激活人中性粒细胞（PMN），而不依赖其cAMP产生和孔形成。 在这个更新的建议，我们将发展这些最近的发现，并集中在AC毒素是必不可少的B的机制和靶组织。百日咳在呼吸道感染的建立。我们将使用纯化毒素或博德特氏菌生物体（均为B）的体外方法。百日咳和B.支气管败血症）的研究，以了解更多关于毒素组成、包装、分泌和递送（SA I）、毒素通过其三种功能（整联蛋白受体占据、cAMP产生和孔形成）对两个主要候选靶组织白细胞（SA II）和呼吸道上皮（SA III）的作用。最后，为了开始将AC毒素的作用与其他重要毒力因子的作用联系起来，我们将评价来自B的其他毒素（百日咳毒素、气管细胞毒素）和粘附素（丝状血凝素、percoven）。百日咳，单独和与AC毒素结合，以更好地理解它们在白细胞和呼吸道上皮（SA IV）中的作用的可能相互作用（增强、协同、拮抗或无作用）。目的是应用AC毒素和其他博德特氏菌毒力因子的信息，更有针对性地研究AC毒素如何导致该属引起的感染和疾病。