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

• 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
• 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

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（由申请方提供）：在慢性阻塞性肺疾病（COPD）患者中，其特征是气道细菌定植，呼吸道病毒的合并感染进一步损害宿主防御，导致细菌过度生长和感染以及疾病加重。我们的初步研究表明，用鼻病毒（RV）（负责大多数呼吸道感染的病毒）预感染分化良好的气道上皮细胞培养物，增加了不可分型的流感嗜血杆菌（NTHI）和铜绿假单胞菌（PA）两者的结合，以及细菌诱导的趋化因子表达。此外，我们发现RV感染极化气道上皮细胞诱导PA的新受体的表达。最后，我们开发了两种新的小鼠模型，这将使我们能够测试是否预先感染RV增加体内细菌感染的易感性。首先，接种RV 1B，一种与低密度脂蛋白受体结合的小组RV，诱导C57/BL 6小鼠的嗜酸性气道炎症和高反应性。其次，我们已经开发了一种小鼠模型COPD的序贯鼻内治疗弹性蛋白酶和脂多糖。我们的初步研究表明，弹性蛋白酶/LPS治疗的“COPD小鼠”预先感染RV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。为此，我们提出以下具体目标：1。确定RV诱导的气道上皮细胞膜的变化，增强细菌粘附和/或内化。我们推测呼吸道上皮细胞的RV感染增加了新细菌受体的表达。2.确定RV和细菌在体内共感染的影响。我们假设：（i）用RV 1B预感染小鼠气道增加了感染小鼠中细菌的持久性;（ii）RV感染增强了正常和弹性蛋白酶/LPS处理的“COPD小鼠”中细菌诱导的炎症;和（iii）RV增加了体内细菌受体的丰度。了解病毒使COPD患者气道易发生继发性细菌感染的基本机制，将改善现有的COPD预防和治疗策略。公共卫生相关性。病毒和细菌的合并感染是慢性肺病（如慢性阻塞性肺病（COPD）和囊性纤维化）患者中常见但知之甚少的现象。了解病毒感染如何促进细菌定植和感染可能会导致预防慢性肺部疾病进展的治疗方法的改进。