Co-infections of rhinovirus and bacteria in chronic lung disorders

慢性肺部疾病中鼻病毒和细菌的双重感染

基本信息

批准号：
7530219
负责人：
Umadevi Sivanappa Sajjan
金额：
$ 19.25万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7530219
关键词：
Address Adherence Autoradiography Bacteria Bacterial Infections Binding Cell Culture Techniques Cell Surface Receptors Cell membrane Cells Chronic Chronic Obstructive Airway Disease Chronic lung disease Cystic Fibrosis Digestion Disease Elastases Epithelial Cells Epithelium Gel Gene Expression Haemophilus influenzae Histologic Host Defense In Vitro Incubated Infection Inflammation Label Lead Lipopolysaccharides Low Density Lipoprotein Receptor Lung Lung diseases Mediating Membrane Membrane Proteins Minor Modeling Mucins Mus Patients Physiological Pilot Projects Predisposition Preventive Pseudomonas aeruginosa Pyroxylin Respiratory Tract Infections Rhinovirus Secondary to Small Interfering RNA Spottings Testing Therapeutic Trypsin Two-Dimensional Gel Electrophoresis Virus Virus Diseases airway inflammation chemokine improved in vivo mouse model neutralizing antibody prevent public health relevance receptor respiratory respiratory virus response two-dimensional

项目摘要

DESCRIPTION (provided by applicant): In patients with chronic obstructive pulmonary disease (COPD), which is characterized by bacterial colonization of the airways, co-infection with respiratory viruses further impairs host defenses, leading to bacterial overgrowth and infection, as well as disease exacerbation. Our pilot studies indicate that pre-infection of well-differentiated airway epithelial cell cultures with rhinovirus (RV), the virus responsible for most respiratory tract infections, increases binding of both non- typeable Hemophilus influenzae (NTHI) and Pseudomonas aeruginosa (PA), as well as bacteria-induced chemokine expression. Further, we have found that RV infection of polarized airway epithelial cells induces the expression of new receptors for PA. Finally, we have developed two new mouse models which will allow us to test whether pre-infection with RV increases the susceptibility to bacterial infection in vivo. First, inoculation with RV1B, a minor group RV which binds to the low-density lipoprotein receptor, induces neutrophilic airway inflammation and hyperresponsiveness in C57/BL6 mice. Second, we have developed a murine model of COPD by sequential intranasal treatment with elastase and lipopolysaccharide. Our pilot studies indicate that elastase/LPS-treated "COPD mice" pre-infected with RV are more susceptible to infection with NTHI. In this application, we propose the general hypothesis that RV increases airway epithelial cell expression of bacterial receptors, thereby predisposing the epithelium to bacterial infection. To address this, we propose the following Specific Aims: 1. Determine RV-induced changes in the airway epithelial cell membrane that potentiate bacterial adherence and/or internalization. We hypothesize that RV infection of airway epithelial cells increases the expression of new bacterial receptors. 2. Determine the effects of co-infection with RV and bacteria in vivo. We hypothesize that: (i) pre- infection of mouse airways with RV1B increases persistence of bacteria in infected mice; (ii) RV infection potentiates bacteria-induced inflammation in normal and elastase/LPS-treated "COPD mice;" and (iii) RV increases the abundance of receptors for bacteria in vivo. Understanding the basic mechanisms by which viruses predispose the airways to secondary bacterial infection in COPD will improve existing preventive and therapeutic strategies for this disease. PUBLIC HEALTH RELEVANCE. Co-infections with virus and bacteria are common but poorly understood phenomena in patients with chronic lung diseases such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis. Understanding how viral infections promote bacterial colonization and infection may lead to improved treatments that prevent progression of chronic lung disease.

描述（由申请人提供）：慢性阻塞性肺病（COPD）患者的特点是气道细菌定植，呼吸道病毒的共同感染会进一步削弱宿主的防御能力，导致细菌过度生长和感染以及疾病恶化。我们的初步研究表明，用鼻病毒（RV）（大多数呼吸道感染的病毒）对分化良好的气道上皮细胞培养物进行预感染，可增加不可分型流感嗜血杆菌（NTHI）和铜绿假单胞菌（PA）的结合，以及细菌诱导的趋化因子表达。此外，我们发现极化气道上皮细胞的 RV 感染诱导 PA 新受体的表达。最后，我们开发了两种新的小鼠模型，这将使我们能够测试 RV 预感染是否会增加体内细菌感染的易感性。首先，接种 RV1B（一种与低密度脂蛋白受体结合的小类 RV），可在 C57/BL6 小鼠中诱导中性粒细胞气道炎症和高反应性。其次，我们通过弹性蛋白酶和脂多糖连续鼻内治疗开发了慢性阻塞性肺病（COPD）小鼠模型。我们的初步研究表明，预先感染 RV 的弹性蛋白酶/LPS 治疗的“COPD 小鼠”更容易感染 NTHI。在本申请中，我们提出了一般假设，即 RV 增加气道上皮细胞细菌受体的表达，从而使上皮易受细菌感染。为了解决这个问题，我们提出以下具体目标： 1. 确定 RV 诱导的气道上皮细胞膜变化，从而增强细菌粘附和/或内化。我们假设气道上皮细胞的 RV 感染会增加新细菌受体的表达。 2.确定RV和细菌在体内同时感染的影响。我们假设：（i）用 RV1B 预先感染小鼠气道会增加受感染小鼠体内细菌的持久性； (ii) RV 感染会增强正常和弹性蛋白酶/LPS 治疗的“COPD 小鼠”中细菌诱导的炎症； (iii) RV 增加体内细菌受体的丰度。了解病毒使慢性阻塞性肺病气道继发细菌感染的基本机制将改善该疾病的现有预防和治疗策略。公共卫生相关性。在慢性阻塞性肺病（COPD）和囊性纤维化等慢性肺部疾病患者中，病毒和细菌的双重感染是常见但人们知之甚少的现象。了解病毒感染如何促进细菌定植和感染可能会改进治疗方法，预防慢性肺病的进展。