Abstract

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.