Loss of Gasdermin D is protective against influenza virus-induced inflammation and mortality

Influenza A virus activates cellular inflammasome pathways, though it remains unknown whether many of the effector proteins downstream of inflammasome activation promote virus clearance or instead promote pathological inflammation. We investigated the role of gasdermin D (GSDMD), a pore-forming inflammasome effector protein that allows cellular release of inflammatory molecules and eventual pyroptotic lysis of cells. GSDMD knockout (KO) mice infected with influenza virus exhibited reduced weight loss and mortality compared to infected wild type (WT) mice. Lung viral titers were similar between genotypes, indicating that GSDMD does not directly affect virus replication. Instead, we observed that GSDMD KO mice had less severe lung inflammation, histopathology, and immune cell infiltration, suggesting that GSDMD promotes tissue-damaging immune responses following infection. Global transcriptomic analysis revealed significant decreases in specific inflammatory gene programs in GSDMD KO lungs, including decreased neutrophil chemotaxis and activation gene signatures, which were confirmed by decreased neutrophil elastase measurements and decreased neutrophil numbers in the lung. Indeed, exogenous depletion of neutrophils starting at day 3 post infection in WT mice recapitulated the protective phenotype observed in GSDMD KO mice, implicating neutrophils as central players in the GSDMD-dependent pathological response to influenza virus. Overall, these findings reveal an important role for GSDMD during influenza virus-induced lung inflammation, pathogenesis, and neutrophil accumulation. Therapeutic interventions targeting the GSDMD/neutrophil axis may provide an effective means to treat severe influenza virus infection. ### Competing Interest Statement The authors have declared no competing interest.