Gasdermin D Inhibits Coronavirus Infection by Promoting the Noncanonical Secretion of Beta Interferon

Pyroptosis, a programmed cell death, functions as an innate immune effector mechanism and plays a crucial role against microbial invasion. Gasdermin D (GSDMD), as the main pyroptosis effector, mediates pyroptosis and promotes releasing proinflammatory molecules into the extracellular environment through pore-forming activity, modifying inflammation and immune responses. While the substantial importance of GSDMD in microbial infection and cancer has been widely investigated, the role of GSDMD in virus infection, including coronaviruses, remains unclear. Enteric coronavirus transmissible gastroenteritis virus (TGEV) and porcine deltacoronavirus (PDCoV) are the major agents for lethal watery diarrhea in neonatal pigs and pose the potential for spillover from pigs to humans. In this study, we found that alphacoronavirus TGEV upregulated and activated GSDMD, resulting in pyroptosis after infection. Furthermore, the fragment of swine GSDMD from amino acids 242 to 279 (242-279 fragment) was required to induce pyroptosis. Notably, GSDMD strongly inhibited both TGEV and PDCoV infection. Mechanistically, the antiviral activity of GSDMD was mediated through promoting the nonclassical release of antiviral beta interferon (IFN-β) and then enhancing the interferon-stimulated gene (ISG) responses. These findings showed that GSDMD dampens coronavirus infection by an uncovered GSDMD-mediated IFN secretion, which may present a novel target of coronavirus antiviral therapeutics.