The Cytopathic BVDV Core Protein Binds with ASC-Enhance the Assembly of Inflammasome Complex and GSDMD-Mediated Pyroptosis

Abstract

Bovine viral diarrhea (BVD) is a globally prevalent infectious disease in cattle caused by bovine viral diarrhea virus (BVDV) and poses a serious threat to the livestock industry. Clinical manifestations of BVD suggest that inflammatory responses are involved in the pathogenesis of BVDV, whereas the underlying molecular mechanisms remain unclear. As a key signaling hub of innate immunity, inflammasomes activate Caspase-1, thereby facilitating the cleavage of Gasdermin D (GSDMD), promoting membrane pore formation and triggering pyroptosis, thereby contributing critically to host antiviral immunity and viral pathogenesis. This study used Madin-Darby bovine kidney (MDBK) cells as a model to compare infection responses between the cytopathic BVDV NADL strain and the non-cytopathic TC strain. The results showed that both strains upregulate the expression of IL-1β and IL-18 and promote the assembly of the NLRP3 inflammasome, indicating activation of upstream inflammasome signaling; however, only the NADL strain markedly induced Gasdermin D (GSDMD) cleavage, membrane pore formation, and pyroptosis. Further mechanistic studies revealed that core protein C (from the NADL strain) interacts with the inflammasome adaptor protein ASC and promotes NLRP3 inflammasome activation, thereby enhancing the secretion of inflammatory cytokines. In summary, this study provides the molecular mechanism by which cytopathic BVDV activates NLRP3 inflammasome-mediated pyroptosis in an ASC-dependent manner through the core protein C, providing new insights into the inflammation-related pathogenic process of BVDV and the differences in infection outcomes of different viral biotypes.