IL-17RA promotes pathologic epithelial inflammation in a mouse model of upper respiratory influenza infection. IL-17RA promotes pathologic epithelial inflammation in a mouse model of upper respiratory influenza infection

The upper respiratory tract (nasopharynx or NP) is the first site of influenza replication, allowing the virus to disseminate to the lower respiratory tract or promoting community transmission. The host response in the NP regulates an intricate balance between viral control and tissue pathology. The hyper-inflammatory responses promote epithelial injury, allowing for increased viral dissemination and susceptibility to secondary bacterial infections. However, the pathologic contributors to influenza upper respiratory tissue pathology are incompletely understood. In this study, we investigated the role of IL-17RA as a modulator of influenza host response and inflammation in the upper respiratory tract. We used a combined experimental approach involving IL-17RA-/- mice and an air-liquid interface (ALI) epithelial culture model to investigate the role of IL-17 response in epithelial inflammation, barrier function, and tissue pathology. Our data show that IL-17RA-/- mice exhibited significantly reduced neutrophilia, epithelial injury, and viral load. The reduced NP inflammation and epithelial injury in IL-17RA-/- mice correlated with increased resistance against co-infection by Streptococcus pneumoniae (Spn). IL-17A treatment, while potentiating the apoptosis of IAV-infected epithelial cells, caused bystander cell death and disrupted the barrier function in ALI epithelial model, supporting the in vivo findings. Overall design: 13 samples

上呼吸道（nasopharynx，简称NP）是流感病毒复制的初始位点，既可介导病毒播散至下呼吸道，亦可推动社区传播。鼻咽部的宿主免疫应答可精细调控病毒清除与组织病理损伤之间的复杂平衡。过度炎症反应会加重上皮损伤，进而加剧病毒播散，并提升宿主继发细菌感染的易感性。然而，流感引发的上呼吸道组织病理损伤的致病机制尚未完全阐明。本研究旨在探究白细胞介素-17受体A（IL-17RA）作为流感宿主应答与上呼吸道炎症调节因子的作用。本研究采用IL-17RA基因敲除（IL-17RA-/-）小鼠与气液界面（air-liquid interface，简称ALI）上皮培养模型相结合的实验策略，以解析IL-17应答在上皮炎症、屏障功能及组织病理损伤中的调控作用。实验数据表明，IL-17RA-/-小鼠的中性粒细胞浸润、上皮损伤程度及病毒载量均显著降低。IL-17RA-/-小鼠鼻咽部炎症与上皮损伤的减轻，与其对肺炎链球菌（Streptococcus pneumoniae，简称Spn）合并感染的抵抗力增强呈显著相关。IL-17A处理虽可增强甲型流感病毒（influenza A virus，简称IAV）感染上皮细胞的凋亡水平，却会诱发旁观者细胞死亡，并破坏气液界面上皮模型的屏障功能，这与体内实验结果一致。实验整体设计：共13份样本