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

Choudhury, Sk Mohiuddin; Ma, Xusheng; Zeng, ZongBo; Luo, Zhikuan; Li, Yuanyuan; Nian, Xiaofeng; Ma, Yonghua; Shi, Zhengwang; Song, Rui; Zhu, Zixiang; Cao, Weijun; Pei, Jingjing; Zheng, Haixue

doi:10.1128/spectrum.02097-21

Cited by 25 publications

(18 citation statements)

References 49 publications

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“…However, in late infection, SVV may reduced caspase-1 expression because 3C pro cleave NLRP3. In pig bone marrow-derived macrophages (BMDMs), SVV infection activate NLRP3 to induces IL-1β secretion and production ( 15 ). On the contrary, our data illustrated that SVV infection inhibits the activation of NLRP3 inflammasome shown as down-regulation of NLRP3, ASC, caspase-1/p10/p20, cleaved-IL-1β and IL-18.…”

Section: Discussionmentioning

confidence: 99%

“…In macrophages and pigs, SVV 3D binds with NLRP3 to activate the NLRP3 inflammasome, on the other hand, SVV 3D protein interacts with IKKα and IKKβ to induce NF-κB activation. Thus promoting IL-1 β transcription and secretion ( 15 ). Our previous studies have proved that SVV can activate innate immune response via RIG-I signaling pathway ( 16 ).…”

Section: Introductionmentioning

confidence: 99%

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Mfn2 is responsible for inhibition of the RIG-I/IRF7 pathway and activation of NLRP3 inflammasome in Seneca Valley virus-infected PK-15 cells to promote viral replication

Deng

Zhu

et al. 2022

Front. Immunol.

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Seneca Valley virus (SVV), a non-enveloped positive single-stranded virus can cause vesicular disease in swine. However, the mechanisms by which SVV activates an innate immune response remain unknown. Mitofusin-2 (MFN2), a mitochondria-shaping protein regulating mitochondrial fusion and fission, plays a crucial role in innate immune responses. But, the roles of Mfn2 in SVV infection have not been elucidated. Here, we show that SVV inhibited Mfn2 expression and NLRP3 inflammasome, activating RIG-I/IRF7 signaling pathway to increase IFN-λ3 expression. Overexpression of Mfn2 inhibited RIG-I/IRF7 signaling pathway, thus decreasing IFN-λ3 expression and promoting SVV replication. Interestingly, overexpression of Mfn2 also activated NLRP3 inflammasome but did not inhibit SVV proliferation. That may mean the RIG-I/IRF7 signaling pathway plays a more important role in SVV proliferation in PK-15 cells. This study could provide important insights into the modulation of host metabolism during SVV infection and provide a strong theoretical basis for a better understanding of the pathogenic mechanism and immune activation mechanism of SVV.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mfn2 is responsible for inhibition of the RIG-I/IRF7 pathway and activation of NLRP3 inflammasome in Seneca Valley virus-infected PK-15 cells to promote viral replication

Deng

Zhu

et al. 2022

Front. Immunol.

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“…Viral 2B and 3C pro suppress type I IFNs production by inducing the degradation of MAVS [ 34 ], while 2C hel and 3C pro inhibit the production of RIG-I-mediated IFN-β by degrading RIG-I [ 10 ]. In addition, 3C pro also degrades the interferon regulatory factors IRF3 and IRF7 [ 35 ], while 3D pol interacts with NLRP3 to induce IL-1β production by activating NF-κB and ion channel signaling [ 36 ]. Although progress has been made in suppressing the type I interferon signaling pathway induced by SVA and its coded proteins, the possibility that the virus inhibits the innate immune system in other ways still needs to be explored.…”

Section: Discussionmentioning

confidence: 99%

Senecavirus A-induced glycolysis facilitates virus replication by promoting lactate production that attenuates the interaction between MAVS and RIG-I

Lin

et al. 2023

PLoS Pathog

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Senecavirus A (SVA)-induced porcine idiopathic vesicular disease has caused huge economic losses worldwide. Glucose metabolism in the host cell is essential for SVA proliferation; however, the impact of the virus on glucose metabolism in host cells and the subsequent effects are still unknown. Here, glycolysis induced by SVA is shown to facilitate virus replication by promoting lactate production, which then attenuates the interaction between the mitochondrial antiviral-signaling protein (MAVS) and retinoic acid-inducible gene I (RIG-I). SVA induces glycolysis in PK-15 cells, as indicated by significantly increased expression of hexokinase 2 (HK2), 6-phosphofructokinase (PFKM), pyruvate kinase M (PKM), phosphoglycerate kinase 1 (PGK1), hypoxia-inducible factor-1 alpha (HIF-1α), and superoxide dismutase-2 (SOD2) in a dose-and replication-dependent manner, and enhanced lactate production, while reducing ATP generation. Overexpression of PKM, PGK1, HIF-1α, and PDK3 in PK-15 cells and high glucose concentrations promote SVA replication, while glycolytic inhibitors decrease it. Inhibition of RLR signaling allowed better replication of SVA by promoting lactate production to attenuate the interaction between MAVS and RIG-I, and regulatory effect of glycolysis on replication of SVA was mainly via RIG-I signaling. SVA infection in mice increased expression of PKM and PGK1 in tissues and serum yields of lactate. Mice treated with high glucose and administered sodium lactate showed elevated lactate levels and better SVA replication, as well as suppressed induction of RIG-I, interferon beta (IFNβ), IFNα, interferon-stimulated gene 15 (ISG15), and interleukin 6 (IL-6). The inhibitory effect on interferons was lower in mice administered sodium oxamate and low glucose compared to the high glucose, indicating that RLR signaling was inhibited by SVA infection through lactate in vitro and in vivo. These results provide a new perspective on the relationship between metabolism and innate immunity of the host in SVA infection, suggesting that glycolysis or lactate may be new targets against the virus.

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“…Theoretically, the combination of SVA and P16 INK4A gene is expected to activate apoptosis-related pathways in multiple dimensions, including endogenous, exogenous, endoplasmic reticulum stress, P53, TNF, and other pathways [ 31 , 32 ]. Given the notably stronger oncolytic effect of SVA-p16 relative to the parental virus, we speculate that overexpression of the p16 gene triggered the activation of additional apoptotic pathways that overlapped with the oncolytic effect of SVA.…”

Section: Discussionmentioning

confidence: 99%

Infectious Recombinant Senecavirus A Expressing p16INK4A Protein

Gong

Zhao

Tang

et al. 2023

IJMS

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Senecavirus A (SVA) is an oncolytic RNA virus, and it is the ideal oncolytic virus that can be genetically engineered for editing. However, there has not been much exploration into creating SVA viruses that carry antitumor genes to increase their oncolytic potential. The construction of SVA viruses carrying antitumor genes that enhance oncolytic potential has not been fully explored. In this study, a recombinant SVA-CH-01-2015 virus (p15A-SVA-clone) expressing the human p16INK4A protein, also known as cell cycle-dependent protein kinase inhibitor 2A (CDKN2A), was successfully rescued and characterized. The recombinant virus, called SVA-p16, exhibited similar viral replication kinetics to the parent virus, was genetically stable, and demonstrated enhanced antitumor effects in Ishikawa cells. Additionally, another recombinant SVA virus carrying a reporter gene (iLOV), SVA-iLOV, was constructed and identified using the same construction method as an auxiliary validation. Collectively, this study successfully created a new recombinant virus, SVA-p16, that showed increased antitumor effects and could serve as a model for further exploring the antitumor potential of SVA as an oncolytic virus.

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

Cited by 25 publications

References 49 publications

Mfn2 is responsible for inhibition of the RIG-I/IRF7 pathway and activation of NLRP3 inflammasome in Seneca Valley virus-infected PK-15 cells to promote viral replication

Mfn2 is responsible for inhibition of the RIG-I/IRF7 pathway and activation of NLRP3 inflammasome in Seneca Valley virus-infected PK-15 cells to promote viral replication

Senecavirus A-induced glycolysis facilitates virus replication by promoting lactate production that attenuates the interaction between MAVS and RIG-I

Infectious Recombinant Senecavirus A Expressing p16INK4A Protein

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