The Role of IL4R Alpha in Neonatal RSV Immunopathology

描述(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3.65亿至5.85亿美元。人类流行病学研究已将初次感染年龄确定为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的年龄会影响以后生活中的呼吸功能-新生小鼠的感染，7d龄，Th2免疫反应的起点，这有助于发展长期的呼吸道功能障碍。年龄对呼吸道合胞病毒感染引起的免疫和肺反应的影响机制(S)仍不清楚。我们的初步数据显示，IL-4ra的表达受发育调节，其在肺MDCs和Th1细胞上的表达随着动物年龄的增长而下降(即在新生儿中表达最高)。此外，在新生儿呼吸道合胞病毒感染期间下调IL-4ra的表达1)抑制初始的Th2偏向免疫反应，2)保护成人免受持续的Th2免疫偏离和继发性RSV感染的肺部病理生理影响。我们的数据支持IL-4ra在生命早期的表达是严重呼吸道合胞病毒感染的关键和新的年龄依赖机制。因此，我们的假设是，发育调节的IL-4ra在新生儿髓系树突状细胞(MDCs)上的表达是导致免疫和肺反应在晚年偏向哮喘型反应的原因。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-4ra水平的升高启动了对RSV的Th2极化免疫反应，并通过新生儿Th1细胞上的IL-4ra信号导致其消融。我们将在以下特定目标中探索这一假说的有效性：目的1将确定MDCs上与年龄相关的IL-4ra表达是否与新生儿RSV感染导致DC功能改变有关，从而导致促进哮喘的DC。我们将利用条件细胞消融和过继转移策略来确定IL-4ra在新生儿MDCS中的功能作用。目的2探讨新生儿呼吸道合胞病毒(RSV)感染时Th1细胞表面IL-4ra水平升高与其特异性消融及新生儿RSV感染后哮喘表型持续存在的关系。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感染过程中Th2诱导的MDC改变所致。这里提出的概念是新的；从这些研究中获得的数据有望对理解RSV介导的哮喘产生积极的范式转换影响。

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.