Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri, Unites States of America.
PLoS Pathog. 2022 Jun 8;18(6):e1010228. doi: 10.1371/journal.ppat.1010228. eCollection 2022 Jun.
Influenza A virus (IAV) preferentially infects conducting airway and alveolar epithelial cells in the lung. The outcome of these infections is impacted by the host response, including the production of various cytokines, chemokines, and growth factors. Fibroblast growth factor-9 (FGF9) is required for lung development, can display antiviral activity in vitro, and is upregulated in asymptomatic patients during early IAV infection. We therefore hypothesized that FGF9 would protect the lungs from respiratory virus infection and evaluated IAV pathogenesis in mice that overexpress FGF9 in club cells in the conducting airway epithelium (FGF9-OE mice). However, we found that FGF9-OE mice were highly susceptible to IAV and Sendai virus infection compared to control mice. FGF9-OE mice displayed elevated and persistent viral loads, increased expression of cytokines and chemokines, and increased numbers of infiltrating immune cells as early as 1 day post-infection (dpi). Gene expression analysis showed an elevated type I interferon (IFN) signature in the conducting airway epithelium and analysis of IAV tropism uncovered a dramatic shift in infection from the conducting airway epithelium to the alveolar epithelium in FGF9-OE lungs. These results demonstrate that FGF9 signaling primes the conducting airway epithelium to rapidly induce a localized IFN and proinflammatory cytokine response during viral infection. Although this response protects the airway epithelial cells from IAV infection, it allows for early and enhanced infection of the alveolar epithelium, ultimately leading to increased morbidity and mortality. Our study illuminates a novel role for FGF9 in regulating respiratory virus infection and pathogenesis.
甲型流感病毒（IAV）优先感染肺部的传导气道和肺泡上皮细胞。这些感染的结果受宿主反应的影响，包括各种细胞因子、趋化因子和生长因子的产生。成纤维细胞生长因子 9（FGF9）是肺发育所必需的，在体外具有抗病毒活性，并且在 IAV 感染早期无症状患者中上调。因此，我们假设 FGF9 可以保护肺部免受呼吸道病毒感染，并评估在传导气道上皮细胞中过表达 FGF9 的小鼠中的 IAV 发病机制（FGF9-OE 小鼠）。然而，我们发现与对照小鼠相比，FGF9-OE 小鼠对 IAV 和仙台病毒感染高度易感。FGF9-OE 小鼠在感染后 1 天（dpi）即可显示出更高和持续的病毒载量、细胞因子和趋化因子表达增加以及浸润免疫细胞数量增加。基因表达分析显示在传导气道上皮细胞中 I 型干扰素（IFN）的特征明显升高，对 IAV 嗜性的分析发现 FGF9-OE 肺部的感染从传导气道上皮急剧转移到肺泡上皮。这些结果表明，FGF9 信号使传导气道上皮在病毒感染时迅速诱导局部 IFN 和促炎细胞因子反应。虽然这种反应可以保护气道上皮细胞免受 IAV 感染，但它允许肺泡上皮的早期和增强感染，最终导致发病率和死亡率增加。我们的研究阐明了 FGF9 在调节呼吸道病毒感染和发病机制中的新作用。
