Novel strategies for PEDV to interfere with host antiviral immunity through Caspase-1

Porcine epidemic diarrhea virus (PEDV), a member of the <i>Coronaviridae</i> family, responsible for substantial morbidity and mortality in neonatal piglets, representing an ongoing threat to the swine industry. The type I interferon (IFN) response is integral to the innate immune system, playing a critical role in host defense against viral infection. However, viruses have evolved diverse strategies to evade or suppress host immune responses to facilitate their replication. In this study, we demonstrate that PEDV targets Caspase-1 to enhance its replication and suppress IFN-β production. PEDV infection increases the expression of Caspase-1 in both tissues and cells. Overexpression of Caspase-1 significantly reduces IFN-β production while promoting PEDV replication. The suppression of IFN-β production by Caspase-1 is mediated through the cleavage of mitochondrial antiviral signaling (MAVS). Specifically, Caspase-1 cleaves MAVS at Asp182, facilitating viral replication and inhibiting IFN-β production. The resulting MAVS fragments, once cleaved, lose their ability to both inhibit viral replication and induce IFN-β production, thereby enabling PEDV proliferation. Additionally, we observe that Caspase-1 exhibits species-specific cleavage effects on MAVS, though its impact on MAVS cleavage remains consistent. This study provides a novel target for anti-PEDV therapeutic strategies.