Respiratory syncytial virus strain differences in bronchiolits and asthma

细支气管炎和哮喘中呼吸道合胞病毒株的差异

• 批准号: 8196528
• 负责人: Martin Lawrence Moore
• 金额: $ 53.18万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8196528
• 关键词: 4 year old; Acute; Acute Disease; Affect; Allergic; Argentina; Asthma; Biological Assay; Biological Models; Bronchiolitis; Cessation of life; Characteristics; Childhood; Childhood Asthma; Chimeric Proteins; Clinical; Collaborations; Data; Development; Disease; Epidemic; Epidemiology; Epithelial; Exhibits; Extrinsic asthma; Functional disorder; Genetic; Genotype; Glycoproteins; Goals; Hospitalization; Hypersensitivity; Immune; Immune response; Immunity; Infant; Infection; Inflammation; Interleukin-13; Laboratories; Lead; Literature; Lower Respiratory Tract Infection; Lung; Measures; Molecular Epidemiology; Mucins; Mucous body substance; Mus; Nasal Lavage Fluid; Obstructive Lung Diseases; Pathogenesis; Pathway interactions; Patients; Pattern; Production; Proteins; Recruitment Activity; Respiration; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Respiratory syncytial virus RSV F proteins; Role; Serologic tests; Severities; Severity of illness; Subgroup; Vaccines; Viral; Viral Bronchiolitis; Virulence; Virulent; Virus; Virus Diseases; Wheezing; acute bronchiolitis; airway inflammation; airway obstruction; chemokine; cohort; cytokine; disease characteristic; early childhood; human disease; in vivo; infancy; inflammatory marker; mouse model; neutrophil; novel strategies; positional cloning; respiratory; response; virus pathogenesis

PROJECT 2: Our long-term goal is to elucidate mechanisms by which respiratory syncytial virus (RSV) contributes to asthma pathogenesis. RSV is the leading cause of infant bronchiolitis and a major cause of asthma attacks. RSV is likely involved in asthma development. Severe RSV bronchiolitis in infancy is associated with childhood asthma. Our data suggest that different RSV strains cause differential acute disease severity, both in infants and in experimentally infected mice. Our central hypothesis is that more virulent RSV strains will be tightly associated with early childhood wheezing and asthma development and cause greater epithelial damage, TH2-type inflammation, and airway mucus expression. Our project represents a synergy between RSV molecular epidemiology and mechanistic mouse models of RSV pathogenesis. It is part of a larger study focusing on mechanisms of bronchiolitis-to-asthma in children. The ReSPIRA (Respiratory Study Protection Infection RSV Asthma) cohort will follow 2000 infants until 3-4 years of age. We expect 20-30% of infants will have RSV lower respiratory tract infection (severe), 35-40% will have mild RSV infection, and 35-40% will have no RSV infection detectable. Clinical characteristics of illness will be defined, including a quantitative bronchiolitis severity score (BSS) and prolonged wheezing. We will genotype the approximately 1000 anticipated RSV isolates from the ReSPIRA cohort. We will construct dendrograms to define genetic relatedness of the RSV strains. In collaboration with Dr. Tina Hartert's group (Vanderbilt), we will analyze RSV genotypes and clinical parameters such as BSS and prolonged wheezing to define the role of RSV strain differences in disease seventy and asthma development. We will measure cytokine/chemokine levels in patient respiratory secretions to define how RSV genotypes impact the host response. We will investigate mechanisms of ReSPIRA RSV strain pathogenesis in a mouse model. We hypothesize that different ReSPIRA RSVs will cause differential lung IL 13 and mucus expression and epithelial damage in mice. We will investigate the role of neutrophils in ReSPIRA RSV infection by neutrophil depletion. We will define the role of RSV fusion protein variability in differential pathogenesis using a RSV reverse genetics strategy.

项目2：我们的长期目标是阐明呼吸道合胞病毒（RSV） 有助于哮喘发病机制。RSV是婴儿细支气管炎的主要原因，也是婴儿毛细支气管炎的主要原因。 哮喘发作RSV可能参与哮喘的发展。婴儿期严重RSV细支气管炎是 与儿童哮喘有关。我们的数据表明，不同的RSV株引起不同的急性呼吸道感染， 在婴儿和实验感染的小鼠中，疾病的严重程度。我们的核心假设是， 强毒RSV株与儿童早期喘息和哮喘的发展密切相关， 导致更大的上皮损伤、TH 2型炎症和气道粘液表达。我们的项目 代表RSV分子流行病学和RSV机制小鼠模型之间的协同作用 发病机制这是一个更大的研究的一部分，重点是儿童细支气管炎哮喘的机制。的 ReSPIRA（呼吸道研究保护感染RSV哮喘）队列将随访2000名婴儿，直至3-4岁 年龄。我们预计20-30%的婴儿将有RSV下呼吸道感染（严重），35-40%将有RSV下呼吸道感染（严重）， 有轻度RSV感染，35-40%将没有RSV感染检测。疾病的临床特征 包括定量细支气管炎严重程度评分（BSS）和持续喘息。我们将 对来自ReSPIRA队列的约1000个预期RSV分离株进行基因分型。了建设一 树状图来定义RSV毒株的遗传相关性。与Tina Hartert博士的团队合作 （范德比尔特），我们将分析RSV基因型和临床参数，如BSS和长期喘息 明确RSV毒株差异在疾病进展和哮喘发展中的作用。我们将测量 患者呼吸道分泌物中的细胞因子/趋化因子水平，以确定RSV基因型如何影响宿主 反应我们将在小鼠模型中研究ReSPIRA RSV株致病机制。我们 假设不同ReSPIRA RSV将导致不同的肺IL 13和粘液表达， 上皮损伤。我们将研究中性粒细胞在中性粒细胞介导的ReSPIRA RSV感染中的作用。 耗尽我们将使用RSV融合蛋白的变异性来确定RSV融合蛋白变异性在不同发病机制中的作用。 反向遗传学策略