Work

IFN-dependent Gsdmd priming induces pyroptosis in coronavirus-infected healthy cells

Year: 2026

Type: article

Abstract: Dysregulated pyroptosis in coronavirus-associated acute respiratory distress syndrome (ARDS) involves intricate crosstalk between viral infection and host inflammatory cascades; however, the detailed mechanism of gasdermin-mediated tissue damage remains poorly defined. Here, using a porcine deltacoronavirus (PDCoV) murine model that faithfully recapitulates human disease, we report a dual-layered pyroptosis amplification circuit that drives ARDS pathology. Mechanistically, PDCoV infection triggers pyroptosis via Nlrp3 inflammasome-dependent cleavage of Gsdmd, while IFN-β acts as an intercellular messenger to induce the transcription factor Irf2 in bystander cells. Irf2 directly binds the Gsdmd promoter to upregulate its transcription, resulting in the formation of a feedforward loop that amplifies pyroptosis and exacerbates alveolar injury. We further developed a combination therapy targeting Irf2 (via siRNA) and Nlrp3 (via MCC950), which synergistically reduced pulmonary viral loads and suppressed IL-1β/IL-18 release in infected mice. Our findings reveal a coordinated transcriptional-proteolytic axis underlying coronavirus-induced ARDS and validate a host-directed strategy to mitigate pyroptosis-associated lung damage. Using a mouse model of coronavirus-induced lung injury, we identify a two-tier mechanism controlling pyroptotic cell death. We show that combined inhibition of NLRP3 and IRF2 reduces inflammatory lung damage more effectively than single target treatment.

Source: Communications Biology

DOI: 10.1038/s42003-026-11091-1