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Volume 41 Issue 3
June 2026
    Citation: Chong Wang, Bingyu Guo, Yilin Li, Xi Zhou, Zongqiang Cui, Yujie Ren. EV-A71 induces GSDME-dependent T-cell pyroptosis: A novel mechanism and MeCbl therapeutic potential .VIROLOGICA SINICA, 2026, 41(3) : 651-661.  http://dx.doi.org/10.1016/j.virs.2026.05.006
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    EV-A71 induces GSDME-dependent T-cell pyroptosis: A novel mechanism and MeCbl therapeutic potential

    • a. State Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan 430071, China;

    • b. University of Chinese Academy of Sciences, Beijing 100049, China

    • Corresponding author: Zongqiang Cui, czq@wh.iov.cn
      Yujie Ren, renyujie@wh.iov.cn
    • Received Date: 03 February 2026
      Accepted Date: 22 May 2026
      Available online: 29 May 2026
    • Enterovirus A71 (EV-A71) is the primary pathogen causing severe hand-foot-and-mouth disease (HFMD) in young children, with T-cell immune dysfunction closely linked to severe clinical outcomes. However, the molecular mechanisms underlying EV-A71-mediated T-cell impairment remain unclear, and no specific therapies are currently available. Here, we investigated the interaction between EV-A71 and T cells, and explored potential targeted therapeutic strategies. Our results showed that EV-A71 efficiently infects T cell lines (Jurkat, EL-4) and primary mouse CD3+ T cells in a dose- and time-dependent manner, inducing T-cell death and upregulating pro-inflammatory cytokines (IL-1β, IL-6, TNF-α). Mechanistically, EV-A71 infection triggers GSDME-dependent pyroptosis in T cells via caspase-3 activation, rather than GSDMD-dependent pyroptosis, as evidenced by genetic ablation and inhibitor experiments. Methylcobalamin (MeCbl), a specific GSDME inhibitor, rescued EV-A71-induced T-cell loss, and significantly improved the survival rate (80%) of EV-A71-infected newborn mice. Furthermore, the combined treatment with MeCbl and AGS-A (a T cell-dependent therapeutic agent) exerted a synergistic protective effect, achieving 90% survival rate in wild-type mice, which was abrogated in T cell-deficient BALB/c-nu-/- mice. Collectively, our findings identify GSDME-dependent T-cell pyroptosis as a key pathogenic mechanism of EV-A71 infection and highlight MeCbl as a promising targeted agent for HFMD treatment, either used alone or in combination with AGS-A.
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      EV-A71 induces GSDME-dependent T-cell pyroptosis: A novel mechanism and MeCbl therapeutic potential

        Corresponding author: Zongqiang Cui, czq@wh.iov.cn
        Corresponding author: Yujie Ren, renyujie@wh.iov.cn
      • a. State Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan 430071, China;
      • b. University of Chinese Academy of Sciences, Beijing 100049, China
      • Received Date: 03 February 2026
      • Accepted Date: 22 May 2026

      Abstract: Enterovirus A71 (EV-A71) is the primary pathogen causing severe hand-foot-and-mouth disease (HFMD) in young children, with T-cell immune dysfunction closely linked to severe clinical outcomes. However, the molecular mechanisms underlying EV-A71-mediated T-cell impairment remain unclear, and no specific therapies are currently available. Here, we investigated the interaction between EV-A71 and T cells, and explored potential targeted therapeutic strategies. Our results showed that EV-A71 efficiently infects T cell lines (Jurkat, EL-4) and primary mouse CD3+ T cells in a dose- and time-dependent manner, inducing T-cell death and upregulating pro-inflammatory cytokines (IL-1β, IL-6, TNF-α). Mechanistically, EV-A71 infection triggers GSDME-dependent pyroptosis in T cells via caspase-3 activation, rather than GSDMD-dependent pyroptosis, as evidenced by genetic ablation and inhibitor experiments. Methylcobalamin (MeCbl), a specific GSDME inhibitor, rescued EV-A71-induced T-cell loss, and significantly improved the survival rate (80%) of EV-A71-infected newborn mice. Furthermore, the combined treatment with MeCbl and AGS-A (a T cell-dependent therapeutic agent) exerted a synergistic protective effect, achieving 90% survival rate in wild-type mice, which was abrogated in T cell-deficient BALB/c-nu-/- mice. Collectively, our findings identify GSDME-dependent T-cell pyroptosis as a key pathogenic mechanism of EV-A71 infection and highlight MeCbl as a promising targeted agent for HFMD treatment, either used alone or in combination with AGS-A.

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