EV-A71 induces GSDME-dependent T-cell pyroptosis: A novel mechanism and MeCbl therapeutic potential

Chong Wang; Bingyu Guo; Yilin Li; Xi Zhou; Zongqiang Cui; Yujie Ren

doi:10.1016/j.virs.2026.05.006

June 2026

. doi: 10.1016/j.virs.2026.05.006

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

肠道病毒71型感染导致T细胞发生GSDME依赖性细胞焦亡的机制研究

王冲 ^a ,
郭冰玉 ^a ,
李奕霖 ^a,b ,
周溪 ^a,b ,
崔宗强 ^a,b,, ,
任玉洁 ^a,b,,

a. 高致病性病毒与生物安全全国重点实验室, 中国科学院武汉病毒研究所, 中国科学院生物安全大科学中心;
b. 中国科学院大学

通讯作者： 崔宗强, czq@wh.iov.cn; 任玉洁, renyujie@wh.iov.cn
收稿日期： 2026-02-03
录用日期： 2026-05-22

摘要

肠道病毒71型（EV-A71）是引起婴幼儿重症手足口病的主要病原体，T细胞免疫功能障碍与疾病重症化密切相关。然而，EV-A71导致T细胞免疫功能损伤的分子机制尚不明确，且缺乏特异性治疗手段。本研究探讨了EV-A71感染导致T细胞功能损伤的分子机制，并探索了靶向治疗策略。结果显示，EV-A71能够以剂量和时间依赖的方式高效感染T细胞系（Jurkat、EL-4）及小鼠的CD3⁺ T细胞，诱导T细胞死亡并显著上调炎性因子IL-1β、IL-6以及TNF-α的表达。进一步研究发现，EV-A71感染通过激活caspase-3引发T细胞发生GSDME依赖性焦亡，而非GSDMD依赖性焦亡，基因敲除和抑制剂实验均证实了这一点。甲钴胺作为GSDME特异性抑制剂，可逆转EV-A71诱导的T细胞损伤，并显著提高EV-A71感染小鼠的存活率（达80%）。此外，甲钴胺与T细胞依赖性治疗药物黄芪甲苷联合应用在野生型小鼠中显示出协同保护作用（存活率达90%），而这种保护效应在T细胞缺陷的BALB/c-nu^-/-小鼠中消失。综上所述，本研究证实了EV-A71导致T细胞发生GSDME依赖性细胞焦亡是其感染致病的关键机制，并提示甲钴胺单用或与黄芪甲苷联用，均可作为手足口病极具前景的免疫治疗策略。
- 肠道病毒71型
- , T淋巴细胞
- , 免疫应答
- , GSDME依赖性细胞焦亡
- , 甲钴胺

EV-A71 induces GSDME-dependent T-cell pyroptosis: A novel mechanism and MeCbl therapeutic potential

Chong Wang ^a ,
Bingyu Guo ^a ,
Yilin Li ^a,b ,
Xi Zhou ^a,b ,
Zongqiang Cui ^a,b,, ,
Yujie Ren ^a,b,,

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

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.
- Enterovirus A71 (EV-A71)
- , T cells
- , Immune responses
- , GSDME-Dependent pyroptosis
- , Methylcobalamin

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