SVA 3D Interacts With NLRP3 To Induce IL-1? Production By Activating NF-?B And Ion Channel Signals

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.It is important for the development of many RNA virus-infected diseases.The primary factors through which the infection becomes inflammation involves inflammasome.Inflammasomes are complexes of two or more proteins activated by infection or other cellular stresses.The activation is responsive to specific pathogens,host cell damage,and other environmental stimuli.Inflammasomes bring about the maturation of various pro-inflammatory cytokines such as IL-18 and IL-1? to mediate the innate immune defence mechanisms.Many viruses and their components,such as encephalomyocarditis virus(EMCV)2B viroporin,the viral RNA of hepatitis C virus,the influenza virus M2 viroporin,the respiratory syncytial virus(RSV),small hydrophobic(SH)viroporin,and the human rhinovirus(HRV)2B viroporin can activate the Nod-like receptor(NLR)family pyrin domaincontaining 3(NLRP3)inflammasome to influence the inflammatory response.On the other hand,several viruses use virus-encoded proteins to suppress inflammation activation,such as the influenza virus NS1 protein and the measles virus(MV)V protein.The NLRP3 inflammasome activation,which activates ASC,Caspase-1 to induce IL-1? secretion,has a crucial part in the host inflammatory response defence against invading pathogen.Seneca virus A(SVA)is a small non-enveloped virus with a positive-sense,single-stranded RNA genome of approximately 7.2 kilobases.As is the case for all RNA viruses,a relatively high rate of genetic mutation should be expected for SVA over time.Taxonomically,SVA belongs to and is the only member of the genus Senecavirus in the family Picornaviridae.The term swine idiopathic vesicular disease(IVD)was coined to designate sporadic cases in which pigs display fluid-filled vesicles and erosions on the snout,lip,oral cavity,tongue,skin,coronary band and interdigital skin with an unknown cause.The occurrence of swine IVD has been described in the US and other countries,including Australia,New Zealand and Italy,since the early 1980 s.All these cases tested negative for well-known vesicular disease pathogens,such as FMDV,SVDV,vesicular exanthema of swine virus(VESV)and vesicular stomatitis virus(VSV).In 2008 and 2012,case reports of swine IVD in which SVA was detected,but not the conventional vesicular disease pathogens mentioned above,was made from the US and Canada,raising speculation that SVA may be a causative agent for vesicular disease.Senecavirus A(SVA)infection induces inflammation and even death in animals.At present,there is no study on the mechanism of SVA-induced inflammation.Here we find that SVA activates the NLRP3 inflammasome assembly.Our results demonstrate that SVA activates the IL-1? production and secretion in BMDCs and other macrophages through the NLRP3 inflammasome signalling cascade.SVA RNA translation involves the activation of the NLRP3 inflammasome.Moreover,we identify that SVA 3D protein is necessary for NLRP3 activation and IL-1? secretion by binding with the NACHT domain of NLRP3 using an amino acid 1-154 aa portion.The SVA 3D protein induces NF-?B activation as the primary signal and via changes of intracellular calcium and potassium concentrations as the second signal to trigger NLRP3-mediated inflammation.Our findings unveil the novel mechanism by which SVA induces NLRP3 inflammasome activation,which causes a complex assembly of inflammasome and secretion of IL-1? and help to contribute to a better understanding of the modulation of host inflammation involved in pathogens invasion as well as prevents the spread of damaging agents to nearby tissues,disposes of cell debris and pathogens and sets the stage for the repair process.