Exacerbation of pertussis airway inflammation and pathology by pertussis toxin

百日咳毒素加剧百日咳气道炎症和病理学

• 批准号: 8577405
• 负责人: NICHOLAS H CARBONETTI
• 金额: $ 30.66万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8577405
• 关键词: ADP ribosylation; Acute; Affect; Anions; Asthma; Bacterial Infections; Bordetella pertussis; Bradykinin; Bradykinin B2 Receptor; Case Study; Cells; Cessation of life; Chronic Obstructive Airway Disease; Collaborations; Communicable Diseases; Coughing; Country; Data; Disease; Epidemic; Epithelial; G Protein-Coupled Receptor Signaling; Genes; Human; Immune response; In Vitro; Individual; Infant; Infection; Inflammation; Inflammation Mediators; Inflammatory Response; Knockout Mice; Lung diseases; Mammalian Cell; Mechanical Ventilators; Mediating; Mucous body substance; Mus; Nature; Neurons; Pathogenesis; Pathology; Peptides; Pertussis; Pertussis Toxin; Pertussis Vaccine; Proteins; Reagent; Respiratory System; Respiratory Tract Infections; Respiratory tract structure; Risk; Role; Signal Pathway; Symptoms; Testing; Therapeutic Intervention; Time; Toxin; Universities; Up-Regulation; Vaccination; Vaccines; Virulence; Virulence Factors; Viscosity; airway epithelium; airway inflammation; airway surface liquid; desensitization; design; effective therapy; experience; in vivo Model; infant death; mouse model; neurophysiology; new therapeutic target; novel; pathogen; prevent; public health relevance; respiratory; respiratory reflex; response; tissue/cell culture; transmission process

DESCRIPTION (provided by applicant): Pertussis (whooping cough) is a respiratory disease of humans caused by acute infection with the bacterial pathogen Bordetella pertussis. In the U.S., despite widespread vaccine use, the number of reported cases in 2012 was at a 60-year high, and many other cases go unreported. Several states experienced their worst pertussis epidemic in over 50 years, with multiple infant deaths and thousands of cases. Individuals suffering from pertussis typically experience debilitating cough episodes that last for weeks, but there is no effective treatment for this disease. B. pertussis infects the respiratory tract and produces a number of toxins that adversely affect the host and modulate host responses. One of these toxins, pertussis toxin (PT), is an important virulence factor uniquely produced by B. pertussis. PT ADP-ribosylates heterotrimeric Gi proteins in mammalian cells, disrupting G protein-coupled receptor (GPCR) signaling pathways and causing a wide range of downstream effects on the cell. We hypothesized that PT contributes to pertussis infection and disease through multiple effects on the host. We previously found that PT has several inhibitory effects on the host immune response, including inhibition of innate immune responses that favor bacterial infection. However, our preliminary data here demonstrate that PT stimulates multiple airway inflammatory responses at the peak of B. pertussis infection, including increased expression of an epithelial anion transporter known as pendrin. Pendrin regulates airway surface liquid volume and mucus viscosity, and is implicated in airway pathology in mouse models of asthma and COPD, and therefore represents a potential contributor to pertussis respiratory pathology. We also have preliminary data that PT increases respiratory levels of the inflammatory mediator bradykinin, a peptide implicated in several airway pathologies including cough, and that PT exacerbates respiratory responses to bradykinin. Therefore, we hypothesize that PT is involved in pertussis airway pathology through multiple effects, including upregulation of factors that contribute to airway pathology (such as pendrin) and exacerbation of respiratory responses to inflammatory mediators (such as bradykinin). Using mouse models of B. pertussis infection combined with complementary in vitro approaches, we will test these hypotheses in two specific aims to determine the roles of these PT-mediated effects in pertussis airway pathology. The broad objective of this project is to understand the role(s) of PT in the respirator pathology of pertussis disease, with a view to identification of possible targets for novel therapeutics to treat and prevent pertussis.

描述（由申请方提供）：百日咳（百日咳）是由细菌病原体百日咳博德特氏菌急性感染引起的人类呼吸道疾病。在美国，尽管广泛使用疫苗，但2012年报告的病例数达到60年来的最高水平，许多其他病例没有报告。几个州经历了50多年来最严重的百日咳疫情，多名婴儿死亡，数千例病例。患有百日咳的个体通常会经历持续数周的虚弱咳嗽发作，但这种疾病没有有效的治疗方法。B。百日咳感染呼吸道并产生许多毒素，这些毒素对宿主产生不利影响并调节宿主反应。百日咳毒素（pertussis toxin，PT）是由B产生的一种重要毒力因子。百日咳。PT ADP-核糖基化哺乳动物细胞中的异源三聚体Gi蛋白，破坏G蛋白偶联受体（GPCR）信号传导途径并对细胞产生广泛的下游效应。我们假设PT通过对宿主的多重作用而导致百日咳感染和疾病。我们先前发现PT对宿主免疫应答具有几种抑制作用，包括抑制有利于细菌感染的先天免疫应答。然而，我们的初步数据表明，PT在B峰刺激多种气道炎症反应。百日咳感染，包括上皮阴离子转运蛋白pendrin的表达增加。Pendrin调节气道表面液体体积和粘液粘度，并涉及哮喘和COPD小鼠模型的气道病理学，因此代表百日咳呼吸病理学的潜在贡献者。我们也有初步的数据，PT增加呼吸水平的炎症介质缓激肽，一种肽牵连在几个气道病理，包括咳嗽，PT加剧呼吸反应缓激肽。因此，我们假设PT通过多种效应参与百日咳气道病理学，包括导致气道病理学的因子（如pendrin）上调和对炎症介质（如缓激肽）的呼吸反应加剧。采用小鼠B.百日咳感染结合互补的体外方法，我们将在两个特定的目标，以确定这些PT介导的作用在百日咳气道病理学中的作用来测试这些假设。该项目的主要目的是了解PT在百日咳呼吸道病理学中的作用，以期确定治疗和预防百日咳的新型疗法的可能靶点。