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；人类 流行病学研究已确定首次感染RSV的年龄是患上 儿童哮喘的发展。我们的实验室和其他实验室使用了新生(即≤7d龄)小鼠 感染模型更接近地模拟呼吸道合胞病毒和人类婴儿免疫系统之间的相互作用。 通过这些模型，我们发现新生儿对rsv的免疫反应有显著差异。 与成年人相比。例如，新生小鼠和人类一样，对RSV感染产生了偏向Th2的反应 婴儿。初生时感染的小鼠再次感染会导致呼吸道炎症，其特征是 中性粒细胞和嗜酸性粒细胞，粘液过度生成，以及呼吸道高反应性，所有这些症状都很严重 人类呼吸道合胞病毒病。我们之前发现，这些年龄相关的反应中有很大一部分是由 IL-4Rα在新生儿髓系树突状细胞和Th2细胞上的表达增加 IL13.在这里，我们的初步数据表明，这种早期的IL13是由于II型增加而引起的 先天淋巴样细胞(ILC2s)和ILC2s的增加是由IL33水平迅速升高所推动的 新生儿呼吸道合胞病毒感染肺。这与呼吸道合胞病毒感染的新生儿产生缺陷的IL-1β有关， 我们认为IL33升高(即缺乏IL1β和/或Caspase1对IL33的负调控 在呼吸道上皮细胞中)。尽管IL33已经在其他疾病状态下被广泛研究，但还没有研究 研究了IL33在新生儿/婴儿免疫系统中RSV致病中的作用。我们的发现导致我们的 目前，新的假说认为，在呼吸道合胞病毒感染期间，新生儿血管内皮细胞早期产生IL-1β导致 过量的肺IL33激活DC，促进Th2偏向的免疫病理机制。我们会 使用来自人类婴儿RSV感染队列的独特样本集来探索这一假设的有效性 通过以下具体目标建立与年龄相关的小鼠模型。目标1将证明新生儿 祖细胞呼吸道上皮细胞(AECs)通过IL33协调RSV的免疫致病。我们还将 证明IL33可以预测婴儿呼吸道合胞病毒病的严重程度。目标2将确定与年龄相关的 血管内皮细胞对IL-1β反应的差异是导致IL-33水平升高和产生更多 用创新的方法靶向定量检测IL33活性形式对新生儿RSV的反应 IL33型变异体的调查。目标3将确定IL33直接激活肺组织的机制 DC刺激幼稚的CD4+T细胞以诱导偏向Th2的反应。年龄相关调节的概念 本文提出的IL33是新的，将提供负责人类婴儿免疫的分子机制 对RSV的反应。此外，从这些研究得出的数据预计将具有积极的范式- 在了解严重RSV疾病方面的影响转移，并应产生新的免疫学靶点以促进进展 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.