Role of Pertussis Toxin in Bordetella pertussis infection

百日咳毒素在百日咳博德特氏菌感染中的作用

• 批准号: 7319649
• 负责人: NICHOLAS H CARBONETTI
• 金额: $ 35.36万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7319649
• 关键词: Adoptive Transfer; Anti-Bacterial Agents; Antibodies; Antibody Formation; Antigens; Bordetella; Bordetella pertussis; Cells; Coughing; Cultured Cells; Data; Defect; Disease; Doctor of Philosophy; Epithelial Cells; Exotoxins; Fibrinogen; GTP-Binding Proteins; Gene Deletion; Gene Expression; Goals; Human; Immune; Immune response; Immunodeficient Mouse; Immunosuppression; In Vitro; Infant; Infection; Inflammatory; Lead; Lung; Mammalian Cell; Mediating; Modeling; Morbidity - disease rate; Mus; Mutant Strains Mice; Neutrophil Infiltration; Organism; Pathogenesis; Pertussis; Pertussis Toxin; Play; Predisposition; Production; Range; Relative (related person); Research Personnel; Respiratory System; Respiratory Tract Infections; Role; Serum; Signal Transduction; Structure; Symptoms; T-Lymphocyte; Testing; Therapeutic; Therapeutic immunosuppression; Transgenic Mice; Virulence Factors; Whooping cough due to unspecified organism; chemokine; cytokine; in vivo; macrophage; mortality; mouse model; mutant; neutrophil; novel therapeutics; pathogen; research study; response; secondary infection

Bordetella pertussis is a gram-negative bacterial pathogen that infects the human respiratory tract, leading to a severe paroxysmal coughing disease known as whooping cough that can be fatal in infants. The mechanisms that this pathogen employs to establish an infection and cause disease are still relatively obscure. In addition, although there has been extensive characterization in vitro of the structure and function of several putative 8. pertussis virulence factors, the roles that these factors play in the host-pathogen interaction to promote infection and disease are poorly understood. The overall goal of this project is to determine the role that one of these factors, pertussis toxin (PT), plays in respiratory tract infection by B. pertussis. PT is an exotoxin produced exclusively by this pathogen and can intoxicate a wide range of mammalian cells in culture, but its role in 8. pertussis infection is largely unknown. By comparing a wild type strain (WT) to a mutant strain (APT) with a deletion of the genes encoding PT in a mouse intranasal infection model, we have preliminary data that PT plays an important and early role in colonization of the respiratory tract by 8. pertussis. At least three different immune responses (early neutrophil recruitment to the lungs, early cytokine and chemokine production in the respiratory tract, and serum antibody responses) to infection with WT appear to be suppressed relative to those after infection with APT. Therefore, we hypothesize that an important role of PT is to suppress the antibacterial immune responsesto 8. pertussis, allowing establishment of the infection with subsequent disease pathogenesis. To test this hypothesis we propose four specific aims: (1) to determine the mechanism of inhibition of neutrophil recruitment to the lungs; (2) to determine the relevant targets of PT activity using chemically- and genetically-altered mice; (3) to determine whether PT suppresses lung antibody and T cell responses after 8. pertussis infection; and (4) to determine whether immunosuppression by PT after 8. pertussis infection enhances susceptibility to secondary infections. Elucidation of the specific roles of PT during 8. pertussis infection will increase our understanding of the pathogenic mechanisms of this organism, and may lead to novel therapeutic approaches to combat pertussis infection and disease.

百日咳杆菌是一种革兰氏阴性细菌病原体，感染人类呼吸道， 导致一种严重的阵发性咳嗽疾病，称为百日咳， 婴儿。这种病原体用来建立感染和引起疾病的机制是 仍然相对模糊。此外，尽管已经在体外广泛表征了 几种推测蛋白结构和功能8.百日咳毒力因子，这些因子的作用 在宿主-病原体相互作用中促进感染和疾病的作用知之甚少。的 本项目的总体目标是确定这些因子之一百日咳毒素（PT）所起的作用 在呼吸道感染B。百日咳。PT是该病原体专门产生的外毒素 并能毒害培养中的多种哺乳动物细胞，但它在8.百日咳感染是 大部分未知。通过将野生型菌株（WT）与具有缺失的突变菌株（APT）进行比较， 在小鼠鼻内感染模型中，我们有初步数据表明PT在小鼠鼻内感染中起作用。 重要的和早期的作用，定植的呼吸道8。百日咳。至少三个不同 免疫应答（早期中性粒细胞向肺的募集，早期细胞因子和趋化因子 呼吸道中的产生，和血清抗体应答）感染WT似乎是 相对于感染APT后的抑制。因此，我们假设一个重要的角色 PT的作用是抑制对8.百日咳，允许建立 感染并导致随后的疾病发病机制。为了验证这一假设，我们提出了四个具体的 目的：（1）确定抑制中性粒细胞向肺募集的机制;（2） 使用化学和遗传改变的小鼠确定PT活性的相关靶标;（3） 确定PT是否抑制肺抗体和T细胞反应后8.百日咳感染;以及 (4)以确定是否免疫抑制PT后8。百日咳感染增强 易继发感染。阐明PT在8.百日咳 感染将增加我们对这种生物体致病机制的了解，并且可能 从而导致对抗百日咳感染和疾病新的治疗方法。