Senecavirus a 3D Interacts with NLRP3 to Induce IL-1β Production by Activating NF-κB 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-1β (IL-1β) plays a pivotal role in inflammatory responses to combat microbes. Although SVA infection can produce inflammatory clinical symptoms, the modulation of IL-1β production by SVA infection remains unknown at present. Here, both and , SVA robustly induced IL-1β production in macrophages and pigs. Infection performed in NOD-, LRR-, and pyrin domain-containing three (NLRP3) knockdown cells indicated that NLRP3 is essential for SVA-induced IL-1β 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-1β secretion. In addition, the SVA 3D protein interacts with IKKα and IKKβ to induce NF-κB activation, which facilitates pro-IL-1β transcription. Meanwhile, 3D induces p65 nucleus entry. Moreover, SVA 3D induces calcium influx and potassium efflux, which triggers IL-1β 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-1β maturation and secretion. In the natural host of pigs, we confirmed that 3D also induced IL-1β 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 SVA infection. 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-1β 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-1β production via the NF-κB signaling pathway and ion channel signal. Our study unveils the mechanism underlying the regulation of inflammasome assembly and production of IL-1β in response to SVA infection that will help better understand the modulation of host inflammation in pathogens invasion and development of the vaccine.