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

基本信息

批准号：
7449671
负责人：
ERIK L HEWLETT
金额：
$ 36.08万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
1980
资助国家：
美国
起止时间：
1980-09-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7449671
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 End Point Epithelial Cells Epithelium Evaluation Facility Construction Funding Category Generations Hemagglutinin Human In Vitro Individual Infection Integrins Lead Learning Leukocytes Lung diseases MAP Kinase Gene MAPK8 gene Macrophage-1 Antigen Mammals Mediating Membrane Modeling Mutation NF-kappa B Nitric Oxide Organism Pathogenesis Permeability Pertussis Pertussis Toxin Phagocytosis Phase Phosphorylation Preparation Production Research Personnel Resistance Respiratory System Role Signal Pathway Signal Transduction Signaling Protein Structure Structure of respiratory epithelium Superoxides Surface TLR4 gene Testing Tissues Toxin Vesicle Virulence Factors Whooping cough due to unspecified organism Work bactericide cell type chemokine cytokine cytotoxicity killings macrophage monocyte monolayer mutant neutrophil novel pertactin prevent programs protein activation protein kinase A kinase receptor release of sequestered calcium ion into cytoplasm research study respiratory

项目摘要

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.

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).它的主要功能被认为是在靶细胞的细胞质膜中易位的AC结构域并产生cAMP超生理量的能力。但是，我们已经证明，AC毒素形成跨膜孔的能力也与巨噬细胞的细胞毒性有关。此外，只需结合毒素与CR3的结合，CR3是一种可以充当AC毒素受体的白细胞整合素，可以激活人类嗜中性粒细胞（PMN），与其营地产生和孔形成无关。在此续签建议中，我们将开发这些最新发现，并关注AC毒素在呼吸道中建立感染中必不可少的AC毒素的机制和靶向组织。我们将使用纯化的毒素或波德氏菌生物（百日咳和支气管杆菌芽孢杆菌）使用体外方法，以了解有关毒素成分，包装，分泌和分泌（SA I）的更多信息，毒素对两个主要候选靶向组织，白细胞（SA II）和呼吸阶层（SA的占领）（SA）的影响（SA）的影响（SA）（SA）（SA）的影响（SA）。生产和孔形成）。最后，为了开始将AC毒素与其他重要的毒力因素的作用联系起来，我们将评估其他毒素（百日咳毒素，气管细胞毒素）和粘附素（丝状血凝集素，痛素），与l. littussis b. feltussis，以及与AC的互动相互作用，以促进AC toxin的相互作用（丝状蛋白蛋白酶），以促进AC toxin的相互作用（丝状血凝集素），以了解AC toxin的互动，以促进AC toxin的相互作用，以增强AC的互动（syjunction）。它们在白细胞和呼吸上皮（SA IV）中的作用。目的是将有关AC毒素和其他Bordetelae毒力因子的信息应用于对AC毒素如何促进该属引起的感染和疾病的更为重点研究。