PRRSV infection activates NLRP3 inflammasome through inducing cytosolic mitochondrial DNA stress.

Porcine reproductive and respiratory syndrome virus (PRRSV) infection causes severe interstitial pneumonia and inflammatory response in piglets and growing pigs. IL-1β is implicated in PRRSV-mediated inflammatory response and the pathogenesis of PRRSV infection. Mitochondria are critical intracellular organelles which is served as signaling platform for antiviral immunity response to participate in immune response of virus infection. The role of mitochondria in PRRSV-mediated inflammatory response and the pathogenesis of PRRSV infection has not been elucidated. Here, our data suggested that PRRSV infection facilitates mitochondrial dysfunction, which induces cytosolic mitochondrial DNA (mtDNA) stress and ROS accumulation, severally activates the NLRP3 inflammasome and NF-κB signaling pathway, and consequently stimulates IL-1β production in PAMs. Furthermore, mtDNA degradation by DNase I abrogates the activation of NLRP3 inflammasome and IL-1β secretion during PRRSV infection. Scavenging ROS significantly inhibits NF-κB signaling activation and the subsequently transcription and secretion of IL-1β. In conclusion, our results indicate that cytosolic mtDNA stress and ROS accumulation after PRRSV infection-induced mitochondrial dysfunction activate NLRP3 inflammasome and NF-κB signaling pathway to promote IL-1β production, revealing a new strategy for vaccine and drug development to PRRSV.