Molecular and Cellular Interactions Between Cigarette Smoke Exposure and RSV

描述(由申请人提供)：在儿童和老年人中，接触香烟烟雾(CS)与呼吸道感染的发病率和严重性增加有关。呼吸道合胞病毒(RSV)可引起婴幼儿严重的毛细支气管炎，并加重成人慢性阻塞性肺疾病(COPD)的病程。CS暴露对病毒免疫和致病机制的分子机制研究尚不深入。我的研究表明，CS暴露对RSV感染后肺部的天然免疫具有令人印象深刻的调节能力。CS可增强呼吸道合胞病毒引起的炎症、肺泡破坏和呼吸道纤维化。这些作用是通过I型干扰素(IFN)和Rig-like Helicase(RLH)抗病毒的先天免疫途径介导的。CS暴露还会导致RSV核酸在肺内持续存在，但不会清除活病毒，我们假设这会慢性激活RLH型先天免疫途径，导致慢性炎症。这一新的机制途径可能解释了COPD患者的炎症反应增强和肺功能恶化，以及COPD稳定期患者出现的慢性肺部炎症。假设-CS与活的或紫外线灭活的RSV以协同方式相互作用，以增加炎症和重塑。这些相互作用是由病毒核酸激活非TLR，Rig-like Helicase(RLH)天然免疫途径介导的。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COPD的慢性炎症和重塑反应。目的1：确定CS和RSV之间的协同作用是否由RLH途径介导。目的：明确I型干扰素(IFNA、IFNb)和I型干扰素途径在CS和RSV诱导的炎症和重塑反应增强中的作用。目的：明确I型干扰素非依赖性机制(S)，通过CS暴露增强紫外线灭活呼吸道合胞病毒的炎症反应。目的4：明确CS暴露对CS和室内空气(RA)暴露肺中活病毒和病毒核酸清除的影响。这笔赠款建议在耶鲁大学开展一项研究导师计划，由肺部炎症和纤维化领域的世界领先者杰克·埃利亚斯教授担任主要赞助人。病毒转录和复制领域公认的领导者乔治·米勒教授将担任共同导师。我们还征集了三位RNA病毒学家的专业知识，他们是彼得·柯林斯博士、杰弗里·卡恩博士和杰克·罗斯。耶鲁大学的一个咨询委员会将提供科学和职业咨询。拟议的研究计划将提供一个令人兴奋的科学环境，Dela Cruz博士可以在其中开始他未来的独立学术生涯。 公共卫生相关性：接触香烟烟雾(CS)与病毒呼吸道感染合并时，会导致更严重的疾病和肺功能恶化，如接触CS的呼吸道合胞病毒(RSV)相关性毛细支气管炎婴儿和患有慢性阻塞性肺疾病(COPD)的成年人。我们发现，CS和RSV暴露都会导致肺炎症和重塑变化的夸大增加，这些变化是由涉及Rig-I样解旋酶(Rig-I-like Helicase)I型干扰素的抗病毒免疫途径和CS暴露导致的外源核酸清除缺陷所介导的。这项在小鼠模型上的拟议工作将成为人类翻译研究的垫脚石，希望为COPD和RSV相关疾病开发新的治疗方法。

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.