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，初始感染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，最初感染RSV的年龄会影响晚年的呼吸功能——新生小鼠在7天大时感染RSV，会引发Th2免疫反应，从而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反应的影响机制尚不清楚。我们的初步数据显示，IL-4Ra的表达受发育调控，随着动物年龄的增长，IL-4Ra在肺mDCs和Th1细胞中的表达下降（即在新生儿中表达最高）。此外，新生儿感染RSV时IL-4Ra表达的下调1)抑制了初始的Th2偏向性免疫反应，2)保护了成人继发性RSV感染时持续的Th2免疫偏差和肺部病理生理。我们的数据支持IL-4Ra在生命早期的表达是严重RSV感染的一个关键和新的年龄依赖性机制。因此，我们的假设是，IL-4Ra在新生儿骨髓树突状细胞（mDCs）上的发育调节表达是导致免疫和肺反应偏向于晚年哮喘型反应的原因。具体来说，我们的初步数据表明了一种独特的机制，即新生儿mDCs上IL-4Ra水平的升高启动了针对RSV的th2极化免疫反应，并通过IL-4Ra作用于新生儿Th1细胞的信号传导导致其消融。我们将在以下具体目标中探索这一假设的有效性：目的1将确定年龄相关的IL-4Ra在mDCs上的表达是否负责新生儿RSV感染中mDC功能的改变，从而导致哮喘促进DC。我们将利用条件细胞消融和过继性转移策略来确定IL-4Ra在新生儿mDCs中的功能作用。目的2将探讨我们的预测，即在新生儿RSV感染期间，新生儿Th1细胞上IL-4Ra水平升高是其特异性消融的原因，也是新生儿RSV感染后哮喘表型持续存在的原因。目的3将证明成年小鼠变应性哮喘的恶化是由于新生儿RSV感染期间形成的Th2诱导mDC的改变。这里提出的概念是新颖的；来自这些研究的数据有望对理解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.