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) 参与了哮喘的发病机制。呼吸道合胞病毒是婴儿毛细支气管炎的主要原因，也是 哮喘发作。呼吸道合胞病毒可能与哮喘的发生有关。婴儿期严重呼吸道合胞病毒毛细支气管炎 与儿童哮喘有关。我们的数据表明，不同的RSV毒株会导致不同的急性 疾病的严重性，无论是在婴儿身上还是在实验感染的老鼠身上。我们的中心假设是 强毒的RSV毒株将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、TH2型炎症和呼吸道粘液表达。我们的项目 代表了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。这是一项更大的研究的一部分，该研究专注于儿童毛细支气管炎到哮喘的机制。这个 Respira(呼吸道研究保护感染RSV哮喘)队列将跟踪2000名婴儿直到3-4岁 年纪大了。我们预计20%-30%的婴儿会有RSV下呼吸道感染(严重)，35%-40%的婴儿会 有轻微的呼吸道合胞病毒感染，35-40%将没有检测到呼吸道合胞病毒感染。疾病的临床特征 将进行定义，包括定量毛细支气管炎严重程度评分(BSS)和持续喘息。我们会 大约1000个预期的呼吸道合胞病毒分离株的基因分型。我们将建造 用树状图确定RSV毒株的遗传亲缘关系。与蒂娜·哈特特博士的团队合作 (Vanderbilt)，我们将分析RSV基因类型和临床参数，如血瘀证和持续喘息。 明确RSV株的差异在疾病和哮喘发生中的作用。我们将衡量 患者呼吸道分泌物中细胞因子/趋化因子水平确定RSV基因型别如何影响宿主 回应。我们将在小鼠模型中研究呼吸道合胞病毒株致病的机制。我们 假设不同的呼吸综合征将导致不同的肺IL 13和粘液表达和 小鼠皮肤上皮损伤。我们将研究中性粒细胞在中性粒细胞感染呼吸道合胞病毒中的作用。 耗尽。我们将使用RSV来确定RSV融合蛋白的可变性在不同发病机制中的作用 反向遗传学策略。