Senecavirus a 3D Interacts with NLRP3 to Induce IL-1 beta Production by Activating NF-kappa B and Ion Channel Signals

Senecavirus A (SVA) infection induces inflammation in animals, such as fever, diarrhea, vesicles and erosions, and even death. The inflammatory cytokine interleukin-1 beta (IL-1 beta) plays a pivotal role in inflammatory responses to combat microbes. Although SVA infection can produce inflammatory clinical symptoms, the modulation of IL-1 beta production by SVA infection remains unknown at present. Here, both in vitro and in vivo, WA robustly induced IL-1 beta production in macrophages and pigs. Infection performed in NOD-, LRR-, and pyrin domain-containing three (NLRP3) knockdown cells indicated that NLRP3 is essential for WA-induced IL-1 beta secretion. Importantly, we identified that the 1 to 154 amino acid (aa) portion of SVA 3D binds to the NLRP3 NACHT domain to activate NLRP3 inflammasome assembly and IL-1 beta secretion. In addition, the SVA 3D protein interacts with IKK alpha and IKK beta to induce NF-kappa B activation, which facilitates pro-IL-1 beta transcription. Meanwhile, 3D induces p65 nucleus entry. Moreover, WA 3D induces calcium influx and potassium efflux, which triggers IL-1 beta secretion. Ion channels might be related to 3D binding with NLRP3, resulting in NLRP3-ASC complex assembly. We found that 3D protein expression induced tissue hemorrhage and swelling in the mice model. Consistently, expression of 3D in mice caused IL-1 beta maturation and secretion. In the natural host of pigs, we confirmed that 3D also induced IL-1 beta production. Our data reveal a novel mechanism underlying the activation of the NLRP3 inflammasome after SVA 3D expression, which provides clues for controlling pig's inflammation during the WA infection. IMPORTANCE Inflammation refers to the response of the immune system to viral, bacterial, and fungal infections or other foreign particles in the body, which can involve the production of a wide array of soluble inflammatory mediators. The NLRP3 inflammasome is one of the best-characterized inflammasome leading to IL-1 beta production and maturation. Senecavirus A (SVA) is an oncolytic virus that can cause fever, vesicles and erosions, severe fatal diarrhea, and even the sudden death of piglets. In this study, we demonstrated that 1 to 154 aa of SVA polymerase protein 3D interacts with the NACHT domain of NLRP3 to induce IL-1 beta production via the NF-kappa B signaling pathway and ion channel signal. Our study unveils the mechanism underlying the regulation of inflammasome assembly and production of IL-1 beta in response to SVA infection that will help better understand the modulation of host inflammation in pathogens invasion and development of the vaccine.