Exacerbation of pertussis airway inflammation and pathology by pertussis toxin

描述(申请人提供)：百日咳是一种人类呼吸道疾病，由革兰氏阴性细菌病原体百日咳杆菌急性感染引起。在美国，尽管疫苗被广泛使用，但2010年报告的病例数量达到了60年来的最高水平，许多其他病例没有报告。加州经历了60年来最严重的百日咳疫情，有10名婴儿死亡，9000多例病例。患有百日咳的人通常会经历持续数周的衰弱咳嗽发作，但没有有效的治疗方法。百日咳感染呼吸道并产生大量毒素，对宿主产生不利影响并调节宿主反应。其中百日咳毒素(PT)是百日咳杆菌特有的一种重要毒力因子。PT-ADP-核糖基化哺乳动物细胞中的异源三聚体Gi蛋白，扰乱G蛋白偶联受体(GPCR)信号通路，对细胞产生广泛的下游效应。PT对宿主免疫反应有几种抑制作用，包括对先天免疫反应的抑制 有利于细菌感染的免疫反应。然而，我们的初步数据表明，PT在百日咳杆菌感染的高峰期刺激多种炎症反应，包括编码上皮阴离子转运蛋白的基因表达增加。垂丝蛋白调节呼吸道表面液体体积和黏液粘度，并与哮喘和COPD小鼠模型的呼吸道病理有关，因此是百日咳呼吸道病理的潜在贡献者。我们也有初步数据表明，PT可增加炎症介质缓激肽的呼吸水平，缓激肽与包括咳嗽在内的几种呼吸道病理有关，并且PT可加重对缓激肽的呼吸反应。因此，我们推测PT通过多种作用参与百日咳呼吸道病理过程，包括上调呼吸道上皮细胞的垂蛋白表达和加重对缓激肽的呼吸反应。使用百日咳杆菌感染的小鼠模型和体外互补方法，我们将在两个特定的目标上检验这些假说，以确定这些PT介导的效应在百日咳呼吸道病理中的作用。本项目的总体目标是了解PT在百日咳病呼吸道病理中的作用(S)，以期确定治疗和预防百日咳的新疗法的可能靶点。

DESCRIPTION (provided by applicant): Pertussis (whooping cough) is a respiratory disease of humans caused by acute infection with the gram-negative bacterial pathogen Bordetella pertussis. In the U.S., despite widespread vaccine use, the number of reported cases in 2010 was at a 60-year high, and many other cases go unreported. California experienced its worst pertussis epidemic in 60 years, with 10 infant deaths and over 9000 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. PT has several inhibitory effects on the host immune response, including inhibition of innate immune responses that favor bacterial infection. However, our preliminary data demonstrate that PT stimulates multiple inflammatory responses at the peak of B. pertussis infection, including increased expression of a gene encoding 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 pendrin on airway epithelium and exacerbation of respiratory responses to 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 respiratory pathology of pertussis disease, with a view to identification of possible targets for novel therapeutics to trea and prevent pertussis.