Identifying Asthma-causing RSV Strains and Elucidating the Mechanisms of RSV-mediated Asthma Development

摘要 项目1：鉴定引起哮喘的RSV毒株并阐明RSV的机制- 介导的哮喘发展 呼吸道合胞病毒（RSV）在婴儿期下呼吸道感染是一种常见的风险 这是一个与哮喘密切相关的因素。它也是哮喘的一个危险因素， 建立因果关系的最有力证据。在第一个融资周期中，我们是第一个 研究组对RSV病毒株进行测序和鉴定， 喘息的结果，以及不同的免疫反应和气道微生物模式。这项建议 解决了下一个合乎逻辑的系列问题：（1）这些RSV株与儿童期后期有关吗？ 哮喘的发展，以及（2）我们能否更好地了解RSV介导的哮喘的机制 通过评估宿主对这些菌株的体内和体外反应，为了验证我们的假设， 有RSV株与哮喘发展的风险增加有关，它们通过 引起对婴儿感染的不同急性反应，改变气道和免疫发育， 早期生活微生物模式，我们建议延长纵向随访的1900名儿童参加了 建立了INSPIRE出生队列，在第一个U19资助期结束时将达到4岁。这将使我们 以确认我们已经确定的RSV毒株是否会导致更严重的婴儿发病率和早期喘息 结果也与哮喘以及这些RSV株引起哮喘的途径有关。 我们提出以下建议：（1）确定与6至8岁哮喘发病相关的RSV毒株;（2） 确定RSV毒株在原发性RSV感染期间如何影响宿主微生物环境;（3）评估 原代气道上皮细胞（AEC）对引起哮喘的RSV株的反应;（4）确定RSV诱导的 INSPIRE队列中与哮喘发病相关的免疫反应。最终，这些信息可能 告知疫苗的设计和开发，防止“致弱”RSV毒株诱发 哮喘的发展领导班子在这方面已经工作了15年，有一个到位的 基础设施、已建立的合作关系和正在进行的队列，具有详细的表型和丰富的生物标本 知识库使我们能够成功地进行这项新颖而有影响力的研究。

Abstract PROJECT 1: Identifying Asthma-causing RSV Strains and Elucidating the Mechanisms of RSV- mediated Asthma Development Respiratory syncytial virus (RSV) lower respiratory tract infection during infancy represents a common risk factor that is strongly and consistently associated with asthma. It also represents an asthma risk factor with the strongest body of evidence establishing a causal relationship. In the first funding cycle we have been the first group to ever sequence and identify RSV strains associated with significantly increased risk of recurrent wheezing outcomes, as well as differential immune response and airway microbial patterns. This proposal addresses the next logical series of questions: (1) are these RSV strains associated with later childhood asthma development, and (2) can we better understand the mechanisms of RSV-mediated asthma development by assessing the host response to these strains in vivo and in vitro? To test our hypotheses that there are RSV strains associated with enhanced risk of asthma development, and they act through eliciting differential acute response to infant infection, altering airway and immune development, and early life microbial patterns, we propose to extend longitudinal follow-up of the 1900 children enrolled in the established INSPIRE birth cohort who will be four at the end of the first U19 funding period. This will enable us to confirm if the RSV strains that we have identified to cause more severe infant morbidity and early wheezing outcomes are also associated with asthma, and the pathways through which these RSV strains cause asthma. We propose the following: (1) Identify RSV strains associated with asthma inception at ages 6 to 8 years; (2) Determine how RSV strains impact the host microbial environment during primary RSV infection; (3) Assess primary airway epithelial cell (AEC) response to asthma-causing RSV strains; (4) Determine RSV induced immune responses associated with asthma inception in the INSPIRE cohort. Ultimately this information may inform the design and development of a vaccine that prevents “asthmagenic” RSV strains from predisposing to asthma development. The leadership team has worked in this area for 15 years, have an in-place infrastructure, established collaborations and ongoing cohort with detailed phenotyping and rich biospecimen repository making us well positioned to successfully carry out this novel and impactful study.