Gasdermin B-mediated pyroptosis as a host defense against swine enteric coronaviruses and its antagonism by PEDV

ABSTRACT Gasdermin B (GSDMB), a member of the spore-forming protein gasdermin (GSDM) family, is critical for inflammation and immunity and has been genetically linked to human diseases. Despite its prominent expression at mucosal surfaces, including the gastrointestinal and respiratory tracts, GSDMB’s role in defending against viral pathogens at these barrier tissues remains poorly defined. Here, we reveal that porcine GSDMB (pGSDMB), which is highly expressed in the intestinal epithelium, is a potent innate restriction factor against porcine epidemic diarrhea virus (PEDV), a major enteric coronavirus. Mechanistically, PEDV infection activated caspase-3/6/7 to cleave pGSDMB at D237, generating an active N-terminal fragment (pGSDMB1–237) that triggered pyroptotic cell death to limit viral propagation. Conversely, PEDV evolved a sophisticated countermeasure: the viral nonstructural proteins nsp1 and nsp15 cooperatively suppressed pGSDMB protein expression. This immune evasion required a critical region within nsp1 (86–110 amino acids) and the catalytic endoribonuclease residues (H226 and H241) of nsp15. Importantly, pGSDMB-mediated pyroptosis broadly inhibited replication of diverse swine enteric coronaviruses, including transmissible gastroenteritis virus and porcine deltacoronavirus. Our findings establish GSDMB as an executor of pyroptosis that guards the mucosal interface against coronavirus infection and unveils a novel viral strategy to circumvent this defense, highlighting new avenues for therapeutic intervention against coronaviruses.IMPORTANCEWhile gasdermin B (GSDMB) is genetically associated with mucosal inflammatory diseases like asthma, its function in host defense at mucosal barriers remains an open question. This study defines a critical role for GSDMB as a central innate immune executor against enteric coronaviruses. We demonstrate that porcine GSDMB (pGSDMB) is cleaved during infection to trigger pyroptotic cell death, thereby restricting the replication of porcine epidemic diarrhea virus (PEDV) and other swine enteric coronaviruses. Furthermore, we identify a novel immune evasion strategy whereby PEDV employs its nsp1 and nsp15 proteins to suppress pGSDMB expression, delineating the key viral domains required for this countermeasure. These findings bridge a significant knowledge gap by revealing GSDMB as a guardian of the mucosal interface and inform the development of potential broad-acting therapeutic strategies against coronaviruses.