Antiviral Innate Pathways and Superoxide Dismutase in RSV Bronchiolitis

RSV 毛细支气管炎中的抗病毒先天途径和超氧化物歧化酶

• 批准号: 8621088
• 负责人: Roberto P Garofalo
• 金额: $ 23.19万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8621088
• 关键词: 1 year old; 5 year old; Acute; Affect; Ambulatory Care; Antioxidants; Antiviral Agents; Asthma; Bronchiolitis; Case-Control Studies; Child; Chronic lung disease; Cigarette; Clinical; Clinical Research; Comorbidity; Complex; Cuprozinc Superoxide Dismutase; Data; Dependovirus; Development; Disease; Economic Burden; Environmental Risk Factor; Environmental Tobacco Smoke; Enzymes; Epidemiologic Studies; Epithelial Cells; Exposure to; Family; Future; Gene Transfer; Genetic; Hand; Hospitalization; Host Defense; Human; Immune response; In Vitro; Infant; Infection; Licensing; Life; Lower Respiratory Tract Infection; Lung; Lung Inflammation; Lung diseases; Manganese Superoxide Dismutase; Measures; Mediating; Molecular; Mus; Outpatients; Paramyxoviridae; Pathology; Pathway interactions; Pneumonia; Predisposition; Proteins; RNA Viruses; Reactive Oxygen Species; Relative (related person); Resistance; Resources; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Risk; Risk Factors; Series; Severities; Severity of illness; Smoke; Superoxide Dismutase; Testing; Therapeutic; Tobacco; Tobacco smoke; Vaccines; Viral; Viral Bronchiolitis; Viral Load result; Virus; Virus Diseases; Virus Replication; Virus Shedding; Visit; Wheezing; Work; airway hyperresponsiveness; base; cigarette smoking; cohort; experience; extracellular; high risk infant; human SOD2 protein; improved; in vivo; infancy; middle childhood; mimetics; mouse model; novel; overexpression; pathogen; prevent; protective effect; public health relevance; research study; respiratory; response; salen; superoxide dismutase 1; virus pathogenesis

DESCRIPTION (provided by applicant): Respiratory syncytial virus (RSV) is the single most important viral pathogen causing acute lower respiratory- tract infections (bronchiolitis) in children. No vaccine or specific therapy is currently licensed to prevent and treat RSV infections. Exposure to environmental tobacco smoke (ETS) has been identified as a risk factor for the development of severe RSV infections, yet the mechanisms that determine ETS and infection co-morbidity are largely unknown. Recent studies support the notion that severity of clinical disease is driven by higher level of RSV replication in the airways and studies by our group have shown that expression and activity of superoxide dismutase (SOD) antioxidant enzymes are significantly decreased in the airways of infants with severe episodes of RSV bronchiolitis, particularly if infants had been exposed to ETS. Surprisingly, our new preliminary data have shown that SOD enzymes are able to inhibit RSV replication in cultured epithelial cells and in experimentally-infected mice. We propose the novel hypothesis that lung SOD enzymes have a previously unrecognized function as host antiviral gene products by limiting RSV replication and shortening viral shedding. Our secondary hypothesis is that expression and antiviral function of such enzymes are reduced/impaired in RSV-infected subjects who are exposed to ETS. In this exploratory project we propose to test these hypotheses by two Specific Aims. In Aim 1, the profile, relative abundance, and activity of SOD proteins will be analyzed in nasopharyngeal secretions (NPS) of infants with RSV infections of different clinical severity and with or without exposure to ETS. SOD levels and activity will be correlated with the concentration (i.e. viral titer/load) of RSV in NPS. In Aim 2, we will test the specific hypothesis that increasing of SOD activity in the lungs will blunt RSV replication and improve airway disease. For that, we will increase SOD expression in the lung by adeno-associated virus (AAV)-mediated gene transfer or by the use of salen-based EUK SOD mimetics, and measure RSV titer (as the main endpoint) in an experimental mouse model of RSV infection and co-exposure to ETS. The protective effect of SOD will be evaluated by examining clinical disease, lung inflammation/pathology, and viral-mediated airway hyperresponsiveness. This project may have important translational implications by suggesting new and more aggressive strategies to treat primary respiratory viral infections in high risk infants (i.e. those exposed to ETS). These therapeutic opportunities will b explored in a future R01 application based on the results of this exploratory project.

描述（由申请人提供）：呼吸道合胞病毒（RSV）是引起儿童急性下呼吸道感染（细支气管炎）的最重要的单一病毒病原体。目前尚无疫苗或特定疗法获准用于预防和治疗 RSV 感染。 暴露于环境烟草烟雾 (ETS) 已被确定为发生严重 RSV 感染的危险因素，但决定 ETS 和感染共病的机制在很大程度上尚不清楚。最近的研究支持这样的观点，即临床疾病的严重程度是由气道中较高水平的 RSV 复制引起的，我们小组的研究表明，患有严重 RSV 细支气管炎的婴儿气道中超氧化物歧化酶 (SOD) 抗氧化酶的表达和活性显着降低，特别是如果婴儿接触过 ETS。令人惊讶的是，我们的新初步数据表明，SOD 酶能够抑制培养上皮细胞和实验感染小鼠中 RSV 的复制。我们提出了一个新的假设，即肺 SOD 酶作为宿主抗病毒基因产物，通过限制 RSV 复制和缩短病毒脱落，具有以前未被认识的功能。我们的第二个假设是，在暴露于 ETS 的 RSV 感染受试者中，此类酶的表达和抗病毒功能会减少/受损。在这个探索性项目中，我们建议通过两个具体目标来检验这些假设。在目标 1 中，将分析不同临床严重程度且接触或未接触 ETS 的 RSV 感染婴儿的鼻咽分泌物 (NPS) 中 SOD 蛋白的概况、相对丰度和活性。 SOD 水平和活性与 NPS 中 RSV 的浓度（即病毒滴度/载量）相关。在目标 2 中，我们将检验以下具体假设：肺部 SOD 活性的增加将削弱 RSV 复制并改善气道疾病。为此，我们将通过腺相关病毒 (AAV) 介导的基因转移或使用基于 salen 的 EUK SOD 模拟物来增加肺部 SOD 表达，并在 RSV 感染和共同暴露于 ETS 的实验小鼠模型中测量 RSV 滴度（作为主要终点）。 SOD 的保护作用将通过检查临床疾病、肺部炎症/病理学和病毒介导的气道高反应性来评估。该项目可能会提出新的、更积极的策略来治疗高危婴儿（即接触 ETS 的婴儿）的原发性呼吸道病毒感染，从而具有重要的转化意义。这些治疗机会将在未来的 R01 应用中根据该探索性项目的结果进行探索。