Mechanisms and Enviromental Determinants of Rhinovirus Illness Severity

描述（如申请人所提供）：最近利用基于PCR的诊断的研究表明，鼻病毒（HRV）是下呼吸道疾病的重要原因，包括细支气管炎、流感样疾病和慢性肺部疾病的恶化， 哮喘、囊性纤维化和慢性阻塞性肺病（COPD）。此外，生命头三年的HRV喘息性疾病是随后哮喘的最强风险因素之一。缺乏针对更严重的HRV疾病和哮喘恶化的特定治疗和预防策略是一个主要的未满足的医疗需求。为了解决这一治疗差距，我们提出了一个新的计划，三个相互关联的项目，以确定危险因素 与病毒、宿主免疫反应和环境相关的致病机制决定了HRV疾病的严重程度。临床 该计划的核心是拟议的威斯康星州婴儿免疫和疾病监测队列（“WISC”，项目1），该队列将定义自然发生的干预措施、幼儿期的农场暴露如何增强免疫成熟和抗病毒反应，并减少病毒性呼吸道疾病的发病率。定义不同的农场相关的免疫成熟模式，介导对病毒性疾病的保护，将为新的预防方法提供路线图，旨在最大限度地减少在其他环境中长大的儿童的呼吸道发病率。在项目2中，Ann Palmenberg博士及其同事建议使用新的组织培养系统和分子方法来定义新描述的HRV-C物种的发病机制，重点是识别细胞受体和独特的2Apro结构和生物化学的临床后果。最后，在项目3中，John Yin博士将使用新技术（荧光标记的HRV和指示细胞系，实时荧光显微镜）来揭示HRV在单细胞中的复制如何刺激免疫反应，并定义扩散到邻近细胞的机制。总的来说，这三个项目将广泛分享临床样本，专业知识和概念进展，以确定治疗和预防HRV感染的新目标。

DESCRIPTION (as provided by applicant): Recent studies utilizing PCR-based diagnostics have demonstrated that rhinovirus (HRV) is an important cause of lower respiratory illness including bronchiolitis, influenza-like illness, and exacerbations of chronic lung diseases such as asthma, cystic fibrosis, and chronic obstructive lung disease (COPD). In addition, HRV wheezing illnesses in the first three years of life are among the strongest risk factors for subsequent asthma. The lack of specific treatments and preventive strategies for more severe HRV illnesses and exacerbations of asthma is a major unmet medical need. To address this therapeutic gap, we propose a novel program of three interrelated projects to identify risk factors and pathogenic mechanisms related to the virus, host immune response, and environment that determine the severity of HRV illnesses. The clinical centerpiece of the program is the proposed Wisconsin Infant Immune & Illness Surveillance Cohort ("WISC", Project 1), which will define how a naturally-occurring intervention, farm exposure in early childhood, enhances immune maturation and antiviral responses, and reduces morbidity from viral respiratory illnesses. Defining distinct farm-related patterns of immune maturation that mediate protection from viral illnesses will provide a road map for new preventive approaches intended to minimize respiratory morbidity for children growing up in other environments. In Project 2, Dr. Ann Palmenberg and colleagues propose to use novel tissue culture systems and molecular approaches to define the pathogenesis of the newly described HRV-C species, focusing on identification of the cellular receptor and clinical consequences of unique 2Apro structure and biochemistry. Finally, in Project 3, Dr. John Yin will use novel techniques (fluorescent-tagged HRVs and indicator cell lines, real-time fluorescent microscopy) to reveal how HRV replication in single cells stimulates immune responses and define mechanisms of spread to neighboring cells. Collectively, these three projects will extensively share clinical samples, expertise and conceptual advances to identify new targets for the treatment and prevention of HRV infections.