Rosli Sarah, Ambrose Rebecca L, Harpur Christopher M, Lam Maggie, Hodges Christopher, Barry Kristian T, West Alison C, Mansell Ashley, Lawlor Kate E, Tate Michelle D
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.
Department of Molecular and Translational Sciences, Monash University, Clayton, VIC, Australia.
Cell Death Dis. 2025 Jun 6;16(1):440. doi: 10.1038/s41419-025-07748-0.
Severe influenza A virus (IAV) infections are associated with hyperinflammation and significant lung damage. Gasdermin E (GSDME) mediates pyroptosis, a lytic and inflammatory type of cell death. Cleavage of GSDME by caspase-3 releases the active N-terminal domain, which subsequently forms transmembrane pores, leading to cell lysis and death. In this study, we investigated a role for GSDME in severe influenza. Infection of human bronchial epithelial cells revealed that IAV induces GSDME cleavage and activation, with the magnitude and kinetics of GSDME activation differing between IAV strains. Caspase-3-mediated GSDME activation preceded and overwhelmed gasdermin D (GSDMD) activation. siRNA silencing in vitro confirmed both gasdermins are active in human bronchial epithelial cells and cooperate to drive IAV responses. IAV infection of mice promoted GSDME cleavage in E-cadherin epithelial cells in vivo at day 3. Mice deficient in GSDME (Gsdme) showed improved survival and greater influenza disease resistance compared to their wildtype littermate controls. Gsdme mice exhibited reduced neutrophil infiltration and levels of cytokines IL-6 and IL-1β in the airways and IL-6, TNF, and IFNγ in the serum. This was accompanied by reduced viral loads, lung pathology, and epithelial cell death. Together, these findings demonstrate a pivotal role for GSDME in severe influenza pathogenesis.
甲型流感病毒（IAV）严重感染与过度炎症反应和显著的肺损伤相关。Gasdermin E（GSDME）介导细胞焦亡，这是一种溶解性和炎症性的细胞死亡类型。caspase-3对GSDME的切割会释放出活性N端结构域，该结构域随后形成跨膜孔，导致细胞裂解和死亡。在本研究中，我们调查了GSDME在严重流感中的作用。对人支气管上皮细胞的感染显示，IAV诱导GSDME的切割和激活，不同IAV毒株之间GSDME激活的程度和动力学有所不同。caspase-3介导的GSDME激活先于并超过了gasdermin D（GSDMD）的激活。体外RNA干扰沉默证实，两种gasdermin在人支气管上皮细胞中均有活性，并协同驱动IAV反应。在第3天，IAV感染小鼠在体内促进了E-钙黏蛋白上皮细胞中GSDME的切割。与野生型同窝对照相比，GSDME缺陷（Gsdme）小鼠的存活率提高，对流感疾病的抵抗力更强。Gsdme小鼠气道中的中性粒细胞浸润以及细胞因子IL-6和IL-1β水平以及血清中的IL-6、TNF和IFNγ水平均降低。这伴随着病毒载量、肺部病理和上皮细胞死亡的减少。总之，这些发现证明了GSDME在严重流感发病机制中起关键作用。
