Host and Viral Determinants of Infant and Childhood Allergy and Asthma

描述（由申请人提供）：本申请的长期目标是确定婴儿呼吸道合胞病毒（RSV）感染与使哮喘发病的宿主反应之间的关系。大量证据表明，在婴儿期经历过严重呼吸道合胞病毒细支气管炎的儿童在儿童期后期发生哮喘的风险更大；然而，疾病严重程度的宿主和病毒决定因素尚未完全确定。同样未知的是，婴儿期轻度rsv引起的疾病是否可以预防儿童哮喘的后续发展。在项目1中，我们利用2000名婴儿的呼吸器研究（Respiratory Study for Protection of Infants from RSV to Asthma）队列来关注宿主对RSV感染的免疫反应以及随后复发性喘息和儿童哮喘的风险。具体而言，在项目1中，我们将a)建立出生后前6个月宿主对RSV感染的表型反应与复发性喘息和哮喘风险之间的关系，b)确定影响RSV感染后幼儿喘息和哮喘发展的RSV感染表型的宿主遗传和免疫反应决定因素。在项目2中，我们将重点关注特定RSV菌株对儿童早期喘息和哮喘发展的贡献。将对从呼吸器队列中分离的RSV菌株进行基因分型，并研究临床参数，如细支气管炎严重程度评分，以及呼吸道分泌物中测量的宿主免疫反应介质，以确定RSV基因型如何影响宿主反应。在项目3中，我们将利用RSV感染小鼠模型来检测前列腺素12 （PGI2）在RSV毒株（01/2-20）气道功能障碍中的作用，该毒株与严重的婴儿细支气管炎有关，并在小鼠中诱导气道病理。我们之前报道过PG12及其通过其受体（IP）的信号传导是RSV A2株感染疾病严重程度的关键决定因素。该项目将确定宿主PGI2在RSV气道发病机制中的作用，并确定目前用于治疗人类疾病的PGI2类似物是否是RSV细支气管炎的靶标。此外，在项目3中，我们将在项目2中使用从呼吸器分离的RSV菌株来确定PGI2作为治疗靶点的普遍性。

DESCRIPTION (provided by applicant): The long term objective of this application is to define the relationship between infant respiratory syncytial virus (RSV) infection and the host response that enables asthma inception. There is abundant evidence that children who experience severe RSV bronchiolitis during infancy are at greater risk for developing asthma later in childhood; however the host and viral determinants of severity of illness are not fully defined. Also unknown is whether mild RSV-induced illness in infancy may protect against the subsequent development of childhood asthma. In Project 1, we utilize the ReSPIRA (Respiratory Study for Protection of Infants from RSV to Asthma) cohort of 2000 infants to focus on host immune responses to RSV infection and the subsequent risk of recurrent wheezing and childhood asthma. Specifically, in Project 1 we will a) establish the relationship between the host phenotypic response to RSV infection in the first 6 months of life and the risk of recurrent wheeze and asthma, and b) identify the host genetic and immune response determinants of the RSV infection phenotype that affect the development of early childhood wheezing and asthma following RSV infection. In Project 2, we will focus on the contribution of specific RSV strains to early childhood wheezing and asthma development. RSV strains isolated from the ReSPIRA cohort will be genotyped and clinical parameters such as bronchiolitis severity score, as well as mediators of the host immune response measured in respiratory secretions will be studied to determine how RSV genotypes impact the host response. In Project 3, we will utilize a mouse model of RSV infection to examine the role of the prostaglandin 12 (PGI2) on airway dysfunction of an RSV strain (01/2-20) that has been associated with severe infant bronchiolitis and which induces airway pathology in the mouse. We previously reported that PG12 and signaling through its receptor (IP) is a critical determinant of severity of illness in RSV strain A2 infection. This project will determine the role of host PGI2 in RSV airway pathogenesis and also determine if a PGI2 analog currently used in the treatment of human disease is a target for RSV bronchiolitis. Further, in Project 3, we will use RSV strains isolated from ReSPIRA in Project 2 to determine the generalizability of PGI2 as a therapeutic target.