Co-infections of rhinovirus and bacteria in chronic lung disorders

描述(申请人提供)：在慢性阻塞性肺疾病(COPD)患者中，以呼吸道细菌定植为特征，与呼吸道病毒合并感染进一步损害宿主防御，导致细菌过度生长和感染，以及疾病恶化。我们的初步研究表明，用鼻病毒(RV)预感染高分化的呼吸道上皮细胞培养物，会增加非分型流感嗜血杆菌(NTHI)和铜绿假单胞菌(PA)的结合，以及细菌诱导的趋化因子的表达。此外，我们还发现RV感染极化的呼吸道上皮细胞可以诱导PA的新受体的表达。最后，我们开发了两个新的小鼠模型，这将使我们能够测试预先感染RV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次要组RV，在C57/BL6小鼠中诱导中性粒细胞呼吸道炎症和高反应性。其次，我们建立了一种小鼠慢性阻塞性肺疾病的模型，采用弹性蛋白酶和脂多糖序贯鼻腔治疗。我们的初步研究表明，预先感染RV的弹性酶/脂多糖处理的“COPD小鼠”更容易感染NTHI。在这一应用中，我们提出了一个普遍的假设，即RV增加了呼吸道上皮细胞细菌受体的表达，从而使上皮细胞更容易受到细菌感染。为了解决这个问题，我们提出了以下具体目标：1.确定RV诱导的呼吸道上皮细胞膜的变化，这些变化增强了细菌的黏附和/或内化。我们假设呼吸道上皮细胞的RV感染增加了新的细菌受体的表达。2.确定轮状病毒与细菌混合感染的体内效应。我们假设：(I)预先感染RV1B的小鼠呼吸道增加了细菌在感染小鼠中的持久性；(Ii)RV感染加强了正常和弹性酶/脂多糖治疗的“COPD小鼠”中细菌诱导的炎症；以及(Iii)RV增加了体内细菌受体的丰度。了解病毒使COPD患者的呼吸道易受继发性细菌感染的基本机制，将改进现有的预防和治疗策略。与公共卫生相关。在慢性阻塞性肺疾病(COPD)和囊性纤维化等慢性肺部疾病患者中，病毒和细菌混合感染是常见但知之甚少的现象。了解病毒感染是如何促进细菌定植和感染的，可能会导致改进预防慢性肺部疾病进展的治疗方法。

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.