The Role of IL4R Alpha in Neonatal RSV Immunopathology

描述（由申请人提供）：呼吸道合胞病毒（RSV）是全球婴儿毛细支气管炎的主要原因，每年的医疗费用估计为3.65 - 5.85亿美元。人类流行病学研究已经确定初次感染的年龄是儿童哮喘发展的独立危险因素。我们之前已经在小鼠模型中证明，初次感染RSV的年龄会影响以后的呼吸功能-新生小鼠感染，d 7 d龄，引发Th 2免疫应答，导致长期气道功能障碍的发展。年龄对RSV感染引起的免疫和肺应答的影响机制尚不清楚。我们的初步数据显示，IL-4 Ra的表达是发育调节的，使得其表达随着动物年龄的增长而在肺mDC和Th 1细胞上下降（即，在新生儿中表达最高）。此外，在新生儿中RSV感染期间IL-4 Ra表达的下调1）抑制初始Th 2偏向的免疫应答和2）保护免于在成人中继发性RSV感染中观察到的持续性Th 2免疫偏离和肺病理生理学。我们的数据支持早期生命中IL-4 Ra的表达是严重RSV感染的关键和新的年龄依赖性机制。因此，我们的假设是，新生儿骨髓树突状细胞（mDC）上IL-4 Ra的发育调节表达是负责在以后的生活中偏向哮喘型反应的免疫和肺反应。具体地说，我们的初步数据表明了一种独特的机制，即新生儿mDCs上IL-4 Ra水平的升高启动了对RSV的Th 2极化免疫应答，并且通过新生儿Th 1细胞上的IL-4 Ra信号传导导致其消融。我们将探讨这一假设的有效性，在以下具体目标：目标1将确定是否年龄相关的表达IL-4 Ra的mDC是负责改变mDC功能在新生儿RSV感染导致哮喘促进DC。我们将利用条件性细胞消融和过继转移策略来确定IL-4 Ra对新生儿mDC的功能作用。目的2将探讨我们的预测，新生儿Th 1细胞上的IL-4 Ra水平升高是负责新生儿RSV感染期间的特异性消融和新生儿RSV感染后哮喘表型的持续存在。目的3将证明成年小鼠过敏性哮喘的加重是由于新生儿RSV感染期间形成的Th 2诱导mDC的改变。本文提出的概念是新颖的;预计从这些研究中获得的数据将对理解RSV介导的哮喘产生积极的范式转变影响。

DESCRIPTION (provided by applicant: Respiratory Syncytial Virus (RSV) is the leading cause of bronchiolitis in infants worldwide with healthcare costs estimated at $365-$585 million per year. Human epidemiological studies have identified age at initial infection as an independent risk factor for the development of childhood asthma. We have previously demonstrated in a mouse model that age of initial infection with RSV influences respiratory function in later life - infection of neonatal mice, d 7d of age, primes for a Th2 immune response that contributes to the development of long-term airways dysfunction. The mechanism(s) underlying the influence of age on the immune and pulmonary responses elicited in response to RSV infection remains obscure. Our preliminary data reveal that expression of IL-4Ra is developmentally regulated such that its expression declines on lung mDCs and Th1 cells as animals age (i.e. expression is highest in the neonate). Furthermore, downregulation of IL-4Ra expression during RSV infection in the neonate 1) inhibits the initial Th2 biased immune response and 2) protects against persistent Th2 immune deviation and pulmonary pathophysiology observed with secondary RSV infection in the adult. Our data support the expression of IL-4Ra in early life as a critical and novel age-dependent mechanism of severe RSV infection. Therefore, our hypothesis is that developmentally regulated expression of IL-4Ra on neonatal myeloid dendritic cells (mDCs) is responsible for biasing immune and pulmonary responses towards asthmatic type responses in later life. Specifically, our preliminary data suggest a unique mechanism whereby elevated levels of IL-4Ra on neonatal mDCs initiates a Th2-polarized immune response to RSV and signaling through IL-4Ra on neonatal Th1 cells results in their ablation. We will explore the validity of this hypothesis in the following specific aims: Aim 1 will determine if age-related expression of IL-4Ra on mDCs is responsible for altered mDC function in neonatal RSV infection resulting in an asthma-promoting DC. We will leverage conditional cell ablation and adoptive transfer strategies to determine the functional role of IL-4Ra on neonatal mDCs. Aim 2 will explore our prediction that elevated levels of IL-4Ra on neonatal Th1 cells are responsible for their specific ablation during neonatal RSV infection and for the persistence of the asthma phenotype following neonatal RSV infection. Aim 3 will demonstrate that exacerbation of allergic asthma in adult mice is due to an altered Th2- inducing mDC formed during neonatal RSV infection. The concepts presented here are novel; and the data derived from these studies are expected to have a positive paradigm-shifting impact in understanding RSV- mediated asthma.