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），它将确定如何自然发生的干预，农场暴露在幼儿期，提高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。 相关性：鼻病毒，最初被称为“普通感冒病毒”，也会引起下呼吸道疾病，如儿童喘息，流感样疾病，以及哮喘和COPD的恶化。不幸的是，没有治疗或疫苗可用于HRV感染。我们建议确定HRV疾病严重程度的新的环境和分子决定因素，作为新的治疗策略的基础。 项目1：养殖环境对免疫成熟和呼吸系统健康的影响 项目负责人（PL）：热尔恩，詹姆斯 描述（如申请人所提供）：本提案的主要目标是更好地了解免疫成熟及其与病毒性呼吸道感染疾病严重程度的关系。病毒性呼吸道感染（VRI）对婴儿的健康构成重大风险。对于这些常见的儿童感染，几乎没有治疗方法或有效的疫苗存在， 发病率和死亡率在生命的第一个五年。因此，VRI是一个重要的公共 健康问题影响到受影响儿童的生活质量，增加了工作场所和保健利用方面的社会压力。此外，VRI似乎具有长期持续的健康影响，例如在一些儿童中导致慢性过敏性疾病的发展。独特的是，来自梅萨的未发表数据表明，与非农业儿童相比，农业儿童在生命的头两年呼吸道感染显著减少。这些影响与世界各地发表的研究结果相一致，即农场暴露降低了儿童过敏和哮喘的风险。值得注意的是，过敏原致敏性的发展和对VRI的最高脆弱性与免疫系统的成熟阶段相一致，并且有证据表明，农场暴露增强了先天免疫和T调节（Treg）细胞功能的发展。我们假设农场暴露通过增强先天性抗病毒免疫和Treg功能的发展来降低幼儿VRI的风险。为了验证这一假设，我们将开发一个独特的出生队列研究，从威斯康星州的农场和非农场家庭内梅萨。将以纵向方式沿着VRI和过敏性致敏监测，使用功能测定来确定先天性和Treg细胞成熟。更好地了解环境暴露如何促进对VRI的抵抗力，并通过对免疫成熟的影响减少过敏性疾病，将有助于制定新的策略，为生活在其他地方的人带来农场暴露的好处。除了解决这些研究目标外，该项目还将作为广泛表征的临床标本（气道上皮细胞，鼻病毒的临床分离株）的来源，这将使机制研究能够定义导致临床疾病严重程度的宿主-病毒相互作用。 相关性：病毒性呼吸道感染（VRI）普遍存在，在生命早期引起显著的发病率和死亡率，并且缺乏有效的疫苗或疗法。在生命早期的农场暴露似乎可以促进免疫成熟，我们有新的数据表明，农场儿童的呼吸道疾病明显减少。在这项提案中，我们将组建一个新的出生队列，以更好地影响免疫成熟和病毒性呼吸道疾病。本研究的目的是确定治疗和预防VRI的新靶点。

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. RELEVANCE: Rhinoviruses, originally known as "common cold viruses", also cause lower respiratory illnesses such as childhood wheezing, influenza-like illness, and exacerbations of asthma and COPD. Unfortunately, no treatments or vaccines are available for HRV infections. We propose to identify new environmental and molecular determinants of HRV illness severity that will serve as a basis for new treatment strategies. Project 1: Impact of Farming Environment on Immune Maturation and Respiratory Health Project Leader (PL): Gern, James DESCRIPTION (as provided by applicant): The major goal of this proposal is to better understand immune maturation and its relationship to viral respiratory infection disease severity. Viral respiratory infections (VRI) are a significant health risk to infants. These common childhood infections, for which few therapeutics or effective vaccines exist, result in significant morbidity and mortality during the first five years of life. As such, VRIs are a significant public health problem impacting the quality of life of affected children and places increased societal strain in the workplace and on health care utilization. Additionally VRIs appear to have a long lasting health impact, for example in some children resulting in the development of chronic allergic diseases. Uniquely, unpublished data from MESA demonstrate significantly decreased respiratory infections during the first two years of life in farm children compared to non-farm children. These effects parallel published findings from around the world that farm exposures lower the risk of childhood allergies and asthma. Notably, the development of allergen sensitization and highest vulnerability to VRIs coincides with the maturation phase of the immune system, and there is evidence that farm exposures enhance development of innate immunity and T regulatory (Treg) cell function. We hypothesize that farm exposures reduce the risk of VRIs in young children by enhancing the development of innate antiviral immunity and Treg function. To test this hypothesis, we will develop a unique birth cohort study from Wisconsin farm and non-farm families within MESA. Functional assays to define innate and Treg cell maturation will be utilized in a longitudinal manner along with surveillance of VRIs and allergic sensitization. A better mechanistic understanding of how environmental exposures promote resistance to VRIs and diminish allergic diseases through effects on immune maturation will allow for development of new strategies to bring benefits of farm exposures to those who live elsewhere. In addition to addressing these research goals, this project will serve as a source of extensively characterized clinical specimens (airway epithelial cells, clinical isolates of rhinoviruses) that will enable mechanistic studies to define host-virus interactions tht contribute to the severity of clinical illnesses. RELEVANCE: Viral respiratory infections (VRI) are ubiquitous, cause significant morbidity and mortality in early life, and effective vaccines or therapies are lacking. Farm exposures in early life appear to promote immune maturation, and we have new data to show that farm children have significantly fewer respiratory illnesses. In this proposal, we will assemble a novel birth cohort to better farm effects on immune maturation and viral respiratory illnesses. The goal of this study is to identify new targets for the treatment and prevention of VRI.