Excessive inflammation and tissue damage during severe influenza A virus (IAV) infection can lead to the development of fatal pulmonary disease. Pyroptosis is a lytic and pro-inflammatory form of cell death executed by the pore-forming protein gasdermin D (GSDMD). In this study, we investigated a potential role for GSDMD in promoting the development of severe IAV disease. IAV infection resulted in cleavage of GSDMD in vivo and in vitro in lung epithelial cells. Mice genetically deficient in GSDMD (Gsdmd^−/−) developed less severe IAV disease than wildtype mice and displayed improved survival outcomes. GSDMD deficiency significantly reduced neutrophil infiltration into the airways as well as the levels of pro-inflammatory cytokines TNF, IL-6, MCP-1, and IL-1α and neutrophil-attracting chemokines CXCL1 and CXCL2. In contrast, IL-1β and IL-18 responses were not largely impacted by GSDMD deficiency. In addition, Gsdmd^−/− mice displayed significantly improved influenza disease resistance with reduced viral burden and less severe pulmonary pathology, including decreased epithelial damage and cell death. These findings indicate a major role for GSDMD in promoting damaging inflammation and the development of severe IAV disease.

严重甲型流感病毒 (IAV) 感染期间的过度炎症和组织损伤可导致致命的肺部疾病。焦亡是细胞死亡的一种溶解性和促炎性形式，由成孔蛋白gasdermin D (GSDMD) 执行。在这项研究中，我们研究了 GSDMD 在促进严重 IAV 疾病发展中的潜在作用。IAV 感染导致体内和体外肺上皮细胞中 GSDMD 的裂解。与野生型小鼠相比，基因缺陷 GSDMD ( Gsdmd ^−/− ) 的小鼠患 IAV 疾病的严重程度较轻，并且生存结果有所改善。GSDMD 缺乏显着减少中性粒细胞浸润气道，以及促炎细胞因子 TNF、IL-6、MCP-1 和 IL-1α 以及中性粒细胞吸引趋化因子 CXCL1 和 CXCL2 的水平。相比之下，GSDMD 缺乏对 IL-1β 和 IL-18 反应的影响不大。此外，Gsdmd ^-/−小鼠表现出显着改善的流感疾病抵抗力，病毒负荷减少，肺部病理减轻，包括上皮损伤和细胞死亡减少。这些发现表明 GSDMD 在促进破坏性炎症和严重 IAV 疾病的发展中发挥着重要作用。