Regulation and Function of IL33 During Neonatal RSV Infection

呼吸道合胞病毒（RSV）是全球婴儿毛细支气管炎的主要原因; 流行病学研究已经确定初次RSV感染时的年龄是RSV感染的独立危险因素， 儿童哮喘的发展。我们的实验室和其他实验室已使用新生（即≤ 7日龄）小鼠 感染模型，以更接近地模拟RSV和人类婴儿免疫系统之间的相互作用。 通过这些模型，我们证明了新生儿对RSV的免疫应答存在显著差异 与成年人相比。例如，新生小鼠对RSV感染产生Th 2偏向性应答，人类也是如此。 婴儿。新生时初次感染的小鼠再感染诱导以下列特征为特征的气道炎症： 嗜中性粒细胞和嗜酸性粒细胞、粘液分泌过多和气道高反应性，所有这些症状都是严重的 人RSV疾病。我们以前发现，这些年龄依赖性反应中的大部分是由 新生儿骨髓树突状细胞（mDC）和Th 2细胞上IL 4 R α水平升高， IL 13。在这里，我们的初步数据表明，这种早期IL 13是由于增加的II型白细胞介素13的表达而诱导的。 先天性淋巴样细胞（ILC 2）和ILC 2的增加是由快速升高的IL 33水平驱动的。 新生儿RSV感染的肺部。这与RSV感染新生儿中IL 1 β产生缺陷相关， 我们认为是IL 33升高的原因（即缺乏IL 1 β和/或半胱天冬酶1对IL 33的负调节 在气道上皮细胞中）。尽管IL 33在其他疾病状态中已被广泛研究，但没有研究表明 研究了IL 33在新生儿/婴儿免疫系统中RSV发病机制中的作用。我们的发现导致我们 目前，一种新的假说认为，新生儿AEC在RSV感染期间早期产生IL 1 β， 过量的肺IL 33激活DC，促进Th 2偏向的免疫发病机制。我们将 使用来自人类婴儿RSV感染队列的独特样本集探索该假设的有效性， 年龄相关的小鼠模型，通过以下具体目标。目的1将证明新生儿 祖气道上皮细胞（AEC）通过IL 33协调RSV免疫发病机制。我们还将 表明IL 33可预测婴儿中RSV疾病的严重程度。目标2将确定是否与年龄有关 AEC对IL 1 β反应的差异导致IL 33水平升高，并产生更多的 活性形式的IL 33在新生儿RSV的反应中使用靶向定量的创新方法 IL 33形式变体研究。目的3将确定IL 33直接激活肺动脉的机制。 DC致敏幼稚CD 4 + T细胞以诱导Th 2偏向性应答。年龄依赖性调节的概念 IL-33是一种新的，它将为人类婴儿的免疫调节提供分子机制。 对RSV的反应此外，这些研究得出的数据预计将具有积极的范式- 改变对理解严重RSV疾病的影响，并应产生新的免疫靶点， 儿科疫苗设计。

Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis in infants worldwide; and human epidemiological studies have identified age at initial RSV infection as an independent risk factor for the development of childhood asthma. Our laboratory, and others, have used neonatal (i.e. ≤7d of age) mouse models of infection to more closely mimic the interaction between RSV and the human infant immune system. With these models, we demonstrated significant differences in the immune response to RSV of neonates compared to adults. For example, neonatal mice mount a Th2-biased response to RSV infection as do human infants. Reinfection of mice initially infected as neonates induces airway inflammation characterized by neutrophils and eosinophils, mucus hyperproduction, and airways hyperreactivity, all symptoms of severe human RSV disease. We previously found that much of these age-dependent responses were mediated by increased levels of IL4Rα on neonatal myeloid dendritic cells (mDCs) and Th2 cells and by early signaling by IL13. Here, our preliminary data demonstrate that this early IL13 is induced as a result of increased type II innate lymphoid cells (ILC2s) and the increase in ILC2s is driven by rapidly elevated levels of IL33 in the neonatal RSV-infected lung. This is correlated with defective IL1β production in RSV-infected neonates, which we believe to be responsible for elevated IL33 (i.e. lack of negative regulation of IL33 by IL1β and/or caspase 1 in airway epithelial cells). Although IL33 has been studied extensively in other disease states, no study has investigated the role of IL33 in RSV pathogenesis in a neonatal/infant immune system. Our findings lead to our current, novel hypothesis that inchoate IL1β production by neonatal AECs during RSV infection results in excessive pulmonary IL33 that activates DCs promoting Th2-biased immunopathogenesis. We will explore the validity of this hypothesis using unique sample sets from human infant RSV infection cohorts and age-relevant mouse models through the following specific aims. Aim 1 will demonstrate that neonatal progenitor airway epithelial cells (AECs) orchestrate RSV immunopathogenesis via IL33. We will also demonstrate that IL33 is predictive of RSV disease severity in infants. Aim 2 will determine if age-related differences in IL1β responses by AECs are responsible for increased IL33 levels and the production of more active forms of IL33 in response to neonatal RSV using innovative methodologies for targeted quantitative investigation of IL33 form variants. Aim 3 will identify mechanisms whereby IL33 directly activates pulmonary DCs to prime naïve CD4+ T cells to induce Th2-biased responses. The concept of age-dependent regulation of IL33 presented here is novel and will provide molecular mechanisms responsible for the human infant immune response to RSV. In addition, the data derived from these studies are expected to have a positive paradigm- shifting impact in understanding severe RSV disease and should yield novel immunological targets to advance pediatric vaccine design.