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<p>Japanese encephalitis virus (JEV), a neurotropic flavivirus, relies heavily on the metabolic pathways of its host for replication. This research explores the involvement of pyruvate kinase M2 (PKM2), a crucial enzyme in glycolysis, in the replication of JEV. Through immunoprecipitation‒mass spectrometry (IP-MS) analysis, we initially identified an interaction between the JEV NS5 protein and host PKM2 in infected human neuronal SK-N-SH cells. This interaction was further validated by coimmunoprecipitation and colocalization assays. We observed that JEV infection led to an increase in PKM2 expression and kinase activity, promoting glycolytic flux, as indicated by elevated extracellular acidification rates (ECARs). PKM2 siRNA-mediated silencing or pharmacologically inhibited glycolysis via 2-deoxyglucose (2-DG) markedly reduced JEV replication in vitro, whereas overexpressing PKM2 or activating it with DASA-58 facilitated viral replication. Additionally, in vivo experiments revealed that treatment with 2-DG decreased viral loads, mitigated neuropathological effects, and increased survival rates in mice infected with JEV. Moreover, the effects of glycolysis inhibition or enhancement on JEV replication were found to be independent of interferon signaling. Overall, these results underscore the importance of PKM2-dependent glycolysis as a vital metabolic checkpoint for JEV replication, providing potential avenues for therapeutic interventions targeting host metabolic pathways to address JEV and similar viral infections.</p>

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Japanese encephalitis virus infection induces PKM2-dependent glycolysis to promote viral replication

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月27日

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  • Siqi Dong,
  • Jiabang Yu,
  • Zhenyu Guo,
  • Xinrui Zhang,
  • Ruiming Hu,
  • Huali Xie,
  • Huansheng Wu,
  • Zheng Chen

摘要

Japanese encephalitis virus (JEV), a neurotropic flavivirus, relies heavily on the metabolic pathways of its host for replication. This research explores the involvement of pyruvate kinase M2 (PKM2), a crucial enzyme in glycolysis, in the replication of JEV. Through immunoprecipitation‒mass spectrometry (IP-MS) analysis, we initially identified an interaction between the JEV NS5 protein and host PKM2 in infected human neuronal SK-N-SH cells. This interaction was further validated by coimmunoprecipitation and colocalization assays. We observed that JEV infection led to an increase in PKM2 expression and kinase activity, promoting glycolytic flux, as indicated by elevated extracellular acidification rates (ECARs). PKM2 siRNA-mediated silencing or pharmacologically inhibited glycolysis via 2-deoxyglucose (2-DG) markedly reduced JEV replication in vitro, whereas overexpressing PKM2 or activating it with DASA-58 facilitated viral replication. Additionally, in vivo experiments revealed that treatment with 2-DG decreased viral loads, mitigated neuropathological effects, and increased survival rates in mice infected with JEV. Moreover, the effects of glycolysis inhibition or enhancement on JEV replication were found to be independent of interferon signaling. Overall, these results underscore the importance of PKM2-dependent glycolysis as a vital metabolic checkpoint for JEV replication, providing potential avenues for therapeutic interventions targeting host metabolic pathways to address JEV and similar viral infections.