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)感染与导致哮喘发病的宿主反应之间的关系。有大量证据表明，在婴儿期经历严重呼吸道合胞病毒毛细支气管炎的儿童在童年后期患哮喘的风险更大；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，婴儿时期由呼吸道合胞病毒引起的轻微疾病是否可以预防儿童哮喘的后续发展。在项目1中，我们利用对2000名婴儿进行的呼吸研究(保护婴儿从呼吸道合胞病毒感染到哮喘)队列来关注宿主对呼吸道合胞病毒感染的免疫反应以及随后复发的喘息和儿童哮喘的风险。具体地说，在项目1中，我们将a)建立在生命的前6个月对RSV感染的宿主表型反应与反复喘息和哮喘风险之间的关系，以及b)确定影响RSV感染后早期儿童喘息和哮喘发展的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毒株对儿童早期喘息和哮喘发展的贡献。从呼吸道队列中分离的RSV毒株将进行基因分型，并将研究毛细支气管炎严重程度评分等临床参数，以及在呼吸道分泌物中测量的宿主免疫反应的介质，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感染的小鼠模型来研究前列腺素12(PGI2)在RSV株(01/2-20)呼吸道功能障碍中的作用，RSV株与严重的婴儿毛细支气管炎有关，并导致小鼠的呼吸道病理。我们以前曾报道，在RSV A2株感染中，PG12及其受体(IP)信号是疾病严重程度的关键决定因素。该项目将确定宿主PGI2在呼吸道合胞病毒呼吸道致病中的作用，并确定目前用于治疗人类疾病的一种PGI2类似物是否为呼吸道合胞病毒毛细支气管炎的靶标。此外，在项目3中，我们将使用项目2中从呼吸道分离的RSV毒株来确定PGI2作为治疗靶点的普适性。

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.