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: 8660610
• 负责人: NICHOLAS H CARBONETTI
• 金额: $ 38.76万
• 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/8660610
• 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（由申请人提供）：百日咳（百日咳）是由急性感染与细菌病原体的bordetella budtussis引起的人类的呼吸道疾病。在美国，尽管使用了广泛的疫苗，但2012年报告的病例数为60年，许多其他病例未报告。几个州在50多年来经历了最严重的百日咳流行病，有多个婴儿死亡和数千例病例。患有百日咳的人通常会经历持续数周的咳嗽发作的使人衰弱，但对这种疾病没有有效的治疗。 B.百日咳感染呼吸道，并产生许多对宿主不利影响和调节宿主反应的毒素。这些毒素之一是百日咳毒素（PT），是百日咳芽孢杆菌独特产生的重要毒力因子。 PT ADP-核糖基在哺乳动物细胞中的异三聚体GI蛋白，破坏G蛋白偶联受体（GPCR）信号通路，并对细胞引起广泛的下游影响。我们假设PT通过对宿主的多种影响来促进百日咳感染和疾病。我们先前发现PT对宿主免疫反应有几种抑制作用，包括抑制有利于细菌感染的先天免疫反应。但是，我们的初步数据表明，PT在百日咳芽孢杆菌感染的峰值上刺激多种气道炎症反应，包括增加称为Pendrin的上皮阴离子转运蛋白的表达。 Pendrin调节气道表面液体体积和粘液粘度，并与哮喘和COPD小鼠模型中的气道病理学有关，因此代表了造成百日咳呼吸道病理学的潜在贡献者。我们还拥有初步数据，即PT增加了炎症性介质性心动激肽的呼吸道水平，这是一种与包括咳嗽在内的多种气道病理相关的肽，PT加剧了对Bradylyinin的呼吸反应。因此，我们假设PT通过多种作用参与百日咳气道病理学，包括上调有助于气道病理学（例如pendrin）的因素（例如pendrin）和加剧对炎症介质（例如胸肌）的呼吸反应。使用链球菌感染的小鼠模型与互补的体外方法结合使用，我们将以两个特定目的测试这些假设，以确定这些PT介导的作用在百日咳气道病理学中的作用。该项目的广泛目的是了解PT在百日咳疾病的呼吸器病理学中的作用，以确定新型治疗剂治疗和预防百日咳的可能靶标。