Molecular and Cellular Interactions Between Cigarette Smoke Exposure and RSV

描述（由申请人提供）：香烟烟雾（CS）暴露与儿童和老年人气道感染的发生率和严重程度增加有关。呼吸道合胞病毒（RSV）在婴儿中引起严重的细支气管炎，并在成人慢性阻塞性肺疾病（COPD）恶化中恶化病程。CS暴露对病毒免疫的分子机制及其发病机制尚不清楚。我的研究表明，接触CS对RSV感染后肺部的先天免疫具有令人印象深刻的调节能力。CS增强RSV引起的炎症、肺泡破坏和气道纤维化。这些作用是由I型干扰素（IFN）和rig样解旋酶（RLH）抗病毒先天免疫途径介导的。CS暴露也会导致RSV核酸在肺部的持续存在，但不会清除活病毒，我们假设这会慢性激活RLH先天免疫途径，导致慢性炎症。这一新的机制途径可能解释了慢性阻塞性肺病患者多次病毒诱导加重的炎症反应增强和肺功能恶化，以及稳定期慢性阻塞性肺病患者的慢性肺炎症。假设- CS以协同方式与活的或紫外线灭活的RSV相互作用，增加炎症和重塑。这些相互作用是通过病毒核酸激活非tlr， rig样解旋酶（RLH）先天免疫途径介导的。CS暴露不会改变活病毒的清除，但允许病毒核酸的持续存在，这有助于通过RLH途径激活慢性阻塞性肺病的慢性炎症和重塑反应。目的1：确定CS和RSV之间的协同相互作用是否通过RLH途径介导。目的2：明确I型干扰素（IFNa, IFNb）和1型IFN通路在CS和RSV诱导的炎症和重塑反应增强中的作用。目的3：确定CS暴露增强对uv灭活RSV的炎症反应的I型干扰素非依赖性机制。目的4：确定暴露于CS和室内空气（RA）暴露的肺部对活病毒和病毒核酸清除的影响。这项资助提出了耶鲁大学的一项研究指导计划，主要赞助人是杰克·伊莱亚斯教授，他是世界上肺炎症和纤维化领域的领导者。乔治·米勒教授，公认的领导者在病毒转录和复制将担任共同导师。我们还邀请了三位RNA病毒学家，彼得·柯林斯，杰弗里·卡恩，还有杰克·罗斯。耶鲁大学的一个咨询委员会将提供科学和职业咨询。拟议的研究计划概述将提供一个令人兴奋的科学环境，其中Dela Cruz博士可以启动他未来的独立学术生涯。

DESCRIPTION (provided by applicant): Cigarette smoke (CS) exposure is associated with increased incidence and severity of airway infections in both children and the elderly. Respiratory syncytial virus (RSV) causes severe bronchiolitis in infants and worsens disease course in chronic obstructive lung disease (COPD) exacerbation in adults. The molecular mechanisms of CS exposure on viral immunity and pathogenesis are not well studied. My studies show that CS exposure has an impressive ability to regulate the innate immunity in the lung after RSV infection. CS enhances the inflammation, alveolar destruction and airway fibrosis caused by RSV. These effects are mediated by type I interferon (IFN) and RIG-like helicase (RLH) antiviral innate immune pathways. CS exposure also results in the persistence of RSV nucleic acids, but not clearance of live virus, in the lung, which we hypothesize chronically activates the RLH innate immune pathways that leads to chronic inflammation. This novel mechanistic pathway may explain the heightened inflammatory response and worsening lung functions in COPD patients with multiple virally-induced exacerbations, and the chronic lung inflammation seen in stable COPD patients. Hypotheses - CS interacts in a synergistic manner with live or UV-inactivated RSV to increase inflammation and remodeling. These interactions are mediated by viral nucleic acid activation of the non-TLR, RIG-like helicase (RLH) innate immune pathway. CS exposure does not alter the clearance of live virus, but allows for the persistence of viral nucleic acids, which contribute to the chronic inflammation and remodeling responses in COPD via RLH pathway activation. Aim 1: Determine if the synergistic interaction between CS and RSV are mediated by RLH pathways. Aim 2: Define the role(s) of type I interferons (IFNa, IFNb) and the type 1 IFN pathway in the enhanced inflammatory and remodeling responses induced by CS and RSV. Aim 3: Define the type I interferon-independent mechanism(s) by which CS exposure enhances the inflammatory response to UV-inactivated RSV. Aim 4: Define the effects of CS exposure on the clearance of live virus and viral nucleic acids in CS- and room air (RA)-exposed lungs. This grant proposes a research mentorship program at Yale University under the primary sponsorship of Professor Jack Elias, a world leader in lung inflammation and fibrosis. Professor George Miller, a recognized leader in viral transcription and replication will serve as co-mentor. We have also enlisted the expertise of three RNA virologists, Drs. Peter Collins, Jeffrey Kahn, and Jack Rose. An advisory committee at Yale will provide scientific and career counseling. The proposed research program as outlined will provide an exciting scientific environment wherein Dr. Dela Cruz can launch his future independent academic career. PUBLIC HEALTH RELEVANCE: Cigarette smoke (CS) exposure when combined with viral respiratory infections results in more severe disease and worsening lung function as seen in CS-exposed infants with respiratory syncytial virus (RSV) associated bronchiolitis and in adults with chronic obstructive pulmonary disease (COPD). We have found that exposure to both CS and RSV leads to an exaggerated increase in lung inflammation and remodeling changes that are mediated by an antiviral immune pathway involving RIG-I-like helicase (RLH) type I interferons and a defect in foreign nucleic acid clearance because of CS exposure. This proposed work in the mouse model will be a stepping stone for human translational research in the hopes of developing new therapeutic approaches for COPD and RSV-related diseases.