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

摘要 项目1：鉴定引起哮喘的呼吸道合胞病毒株并阐明其致病机制。 由哮喘引发的发展 呼吸道合胞病毒(RSV)下呼吸道感染在婴儿期是一种常见的风险 与哮喘密切相关的因素。它也代表了哮喘的危险因素 建立因果关系的最有力的证据。在第一个资金周期中，我们是第一个 小组对与显著增加复发风险相关的RSV毒株进行测序和鉴定 喘息结果，以及不同的免疫反应和呼吸道微生物模式。这项建议 回答下一系列合乎逻辑的问题：(1)这些RSV毒株是否与童年后期有关 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 通过评估宿主在体内和体外对这些菌株的反应来开发？来检验我们的假设 有一些RSV毒株与哮喘发病风险增加有关，它们通过 引起对婴儿感染的不同急性反应，改变呼吸道和免疫发育，以及 早期生命微生物模式，我们建议延长对1900名儿童的纵向随访 建立了INSPIRE出生队列，他们将在第一个U19资助期结束时达到4岁。这将使我们能够 以确认我们已确认的RSV毒株是否会导致更严重的婴儿发病率和早期喘息 结果也与哮喘有关，以及这些RSV毒株引起哮喘的途径。 我们建议如下：(1)确定与6至8岁儿童哮喘发病有关的RSV毒株；(2) 确定RSV株在原发RSV感染期间如何影响宿主微生物环境；(3)评估 原代呼吸道上皮细胞(AEC)对引起哮喘的RSV毒株的反应；(4)测定RSV诱导 INSPIRE队列中与哮喘发病相关的免疫反应。最终，这些信息可能 告知设计和开发一种疫苗，以防止“哮喘”RSV毒株易患上 哮喘的发展。领导班子在这个领域已经工作了15年，有一个到位的 基础设施，已建立的合作和持续的队列，具有详细的表型和丰富的生物样品 资源库使我们处于有利地位，能够成功地开展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.