GSDMD and GSDME exhibit distinct roles in enteric coronavirus PDCoV-induced pyroptosis and inflammatory responses

Porcine deltacoronavirus (PDCoV), an emerging enteric coronavirus with zoonotic potential, typically causes intestinal villous epithelial cell damage with inflammation. Pyroptosis is a recently identified inflammatory form of programmed cell death that has been found to be associated with the pathogenesis of many viruses. However, the effects of PDCoV infection on pyroptosis and the role of pyroptosis in its pathogenesis remain unclear. In this study, we report that PDCoV infection triggers pyroptosis, as demonstrated in porcine ileum epithelial cell lines and intestinal tissues of PDCoV-infected piglets. Although both gasdermin D (GSDMD)- and gasdermin E (GSDME)-mediated pyroptosis were observed during PDCoV infection, GSDME dominated PDCoV-induced pyroptosis and subsequent inflammatory responses. More differently, GSDMD, rather than GSDME, exhibited potent anti-PDCoV activity; however, PDCoV-encoded nonstructural protein 5, a 3C-like protease, cleaved GSDMD, but not GSDME, to abolish the antiviral and pyroptotic functions of GSDMD. Our study elucidates the distinct roles of GSDMD and GSDME in PDCoV-induced pyroptosis and inflammatory responses, providing new insight into the pathogenesis of PDCoV and the potential for anti-PDCoV drug development.IMPORTANCEPyroptosis is a type of programmed cell death mediated by various gasdermins (GSDMs). While previous research has primarily focused on the role of GSDMD in pyroptosis, our study demonstrates that GSDME plays a dominant role in pyroptosis and the concomitant inflammatory responses induced by porcine deltacoronavirus (PDCoV), a newly identified enteric coronavirus with the potential to infect humans. The cleavage of GSDMD by PDCoV 3C-like protease may account for the diminished functionality of GSDMD in PDCoV-induced pyroptosis, which simultaneously disrupts its antiviral potential against PDCoV. These findings reveal the intricate interplay between PDCoV, GSDMD, and GSDME, accelerating the elucidation of PDCoV pathogenicity.