Cytopathic bovine viral diarrhea virus-induced NLRP3 inflammasome activation triggers GSDMD-mediated pyroptosis, amplifying the inflammatory response

Abstract

Bovine viral diarrhea virus (BVDV) is the causative agent of bovine viral diarrhea-mucosal disease, which is characterized by diarrhea, enteritis, and erosion and necrosis of intestinal mucosa, causing substantial economic losses in the cattle industry. Previous research has shown that cytopathic BVDV (cpBVDV) can activate the nucleotide oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome, whereas noncytopathic BVDV (ncpBVDV) cannot. Nonetheless, the role of the NLRP3 inflammasome in inflammatory responses triggered by cpBVDV remains poorly understood. Here, we demonstrated that cpBVDV activates the NLRP3 inflammasome via the ATP-dependent K⁺ channel in bovine peripheral blood mononuclear cells and bovine testicular cells, leading to the maturation of inflammatory cytokine IL-1β. Moreover, cpBVDV-induced NLRP3 inflammasome activation promoted Gasdermin D (GADMD)-mediated pyroptosis, resulting in host cell membrane damage and subsequent release of IL-1β, thereby amplifying the inflammatory response. We also found that NLRP3 inflammasome activation exerts a negative regulatory effect on cpBVDV replication. Additionally, key viral proteins-specifically, C, Erns, and NS5B-were identified as contributors to NLRP3 inflammasome-mediated pyroptosis. Our findings indicate that pyroptosis triggered by cpBVDV-induced NLRP3 inflammasome activation plays a critical role in the pathogenesis of cpBVDV-associated diseases, offering new insights into the mechanisms underlying cpBVDV infection.

Keywords: Cytopathic bovine viral diarrhea virus; GSDMD cleavage; IL-1β; Inflammatory responses; NLRP3 inflammasome.