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: 7151228
• 负责人: NICHOLAS H CARBONETTI
• 金额: $ 36.05万
• 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/7151228
• 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 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

DESCRIPTION (provided by applicant): 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 B. 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 B. pertussis infection is largely unknown. By comparing a wild type strain (WT) to a mutant strain (deltaPT) 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 B. 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 deltaPT. Therefore, we hypothesize that an important role of PT is to suppress the antibacterial immune responses to B. 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 B. pertussis infection; and (4) to determine whether immunosuppression by PT after B. pertussis infection enhances susceptibility to secondary infections. Elucidation of the specific roles of PT during B. 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.

描述（由申请方提供）：百日咳博德特氏菌是一种革兰氏阴性细菌病原体，感染人类呼吸道，导致严重的阵发性咳嗽疾病，称为百日咳，对婴儿可能是致命的。这种病原体用来建立感染和引起疾病的机制仍然相对模糊。此外，虽然已经有了广泛的表征，在体外的结构和功能的几个假定的B。虽然百日咳毒力因子的研究进展缓慢，但这些因子在宿主-病原体相互作用中促进感染和疾病的作用知之甚少。该项目的总体目标是确定这些因子之一百日咳毒素（PT）在B呼吸道感染中的作用。百日咳。PT是一种由该病原体专门产生的外毒素，可使培养的多种哺乳动物细胞中毒，但其在B.百日咳感染在很大程度上是未知的。通过在小鼠鼻内感染模型中比较野生型菌株（WT）与缺失编码PT的基因的突变菌株（deltaPT），我们获得了PT在B的呼吸道定殖中起重要和早期作用的初步数据。百日咳。相对于deltaPT感染后的免疫应答，WT感染的至少三种不同免疫应答（早期中性粒细胞向肺部募集、呼吸道中早期细胞因子和趋化因子产生以及血清抗体应答）似乎受到抑制。因此，我们推测PT的一个重要作用是抑制对B的抗菌免疫应答。百日咳，允许建立具有随后的疾病发病机制的感染。为了验证这一假设，我们提出了四个具体目标：（1）确定抑制中性粒细胞募集到肺部的机制;（2）使用化学和遗传改变的小鼠确定PT活性的相关靶点;（3）确定PT是否抑制B后的肺抗体和T细胞反应。百日咳感染;（4）确定B.百日咳感染增加了继发感染的易感性。阐明PT在B.百日咳感染将增加我们对这种生物体的致病机制的理解，并可能导致对抗百日咳感染和疾病的新的治疗方法。