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Background <p>Severe Omicron cases present profound lymphocytopenia, suggesting variant-specific immune injury.</p> Results <p>We identify CD63 as a conserved T-cell host factor supporting ACE2-independent SARS-CoV-2 entry. Despite lower intracellular viral loads than the ancestral strain, Omicron elicits enhanced T-cell apoptosis largely through a bystander mechanism. Omicron-stimulated epithelial cells secrete GDF15, which upregulates the pro-apoptotic protein BCL2L13 in T cells and thereby remotely accelerates apoptosis in uninfected bystanders. Functionally, recombinant GDF15 increases BCL2L13 and apoptosis, while genetic dampening of BCL2L13 blunts Omicron-specific high-intensity bystander death. In clinical samples, plasma GDF15 associates with mortality, SOFA scores, and lower lymphocyte counts, bridging the epithelial–immune axis to patient outcomes.</p> Conclusions <p>Our data delineate a two-track model of Omicron immune injury—CD63-enabled T-cell entry plus GDF15–BCL2L13-driven bystander apoptosis—that reconciles lower epithelial cytopathicity with deeper T-cell depletion in critical disease. These findings nominate the GDF15–BCL2L13 axis as a mechanistic marker and potential point of intervention.</p>

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Variant-divergent death: Omicron intensifies bystander T-cell apoptosis via GDF15–BCL2L13

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月28日

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  • Chao Gao,
  • Hanbing Chen,
  • Ying Chi,
  • Xinxing Lu,
  • Jiahuang Li,
  • Ying Tang,
  • Ruixuan Yu,
  • Nan Shi,
  • Ling Liu,
  • Jianfeng Xie,
  • Haibo Qiu,
  • Jie Chao,
  • Shufeng Li

摘要

Background

Severe Omicron cases present profound lymphocytopenia, suggesting variant-specific immune injury.

Results

We identify CD63 as a conserved T-cell host factor supporting ACE2-independent SARS-CoV-2 entry. Despite lower intracellular viral loads than the ancestral strain, Omicron elicits enhanced T-cell apoptosis largely through a bystander mechanism. Omicron-stimulated epithelial cells secrete GDF15, which upregulates the pro-apoptotic protein BCL2L13 in T cells and thereby remotely accelerates apoptosis in uninfected bystanders. Functionally, recombinant GDF15 increases BCL2L13 and apoptosis, while genetic dampening of BCL2L13 blunts Omicron-specific high-intensity bystander death. In clinical samples, plasma GDF15 associates with mortality, SOFA scores, and lower lymphocyte counts, bridging the epithelial–immune axis to patient outcomes.

Conclusions

Our data delineate a two-track model of Omicron immune injury—CD63-enabled T-cell entry plus GDF15–BCL2L13-driven bystander apoptosis—that reconciles lower epithelial cytopathicity with deeper T-cell depletion in critical disease. These findings nominate the GDF15–BCL2L13 axis as a mechanistic marker and potential point of intervention.