Epithelial Galectin-3 Induced the Mitochondrial Complex Inhibition and Cell Cycle Arrest of CD8+ T Cells in Severe/Critical COVID-19

Previous research recommended the dramatical reduction in CD8 T cells is really a adding element in poor people prognosis and disease advancement of COVID-19 patients. However, the actual mechanisms aren’t fully understood. Within this study, we conducted Single-cell RNA sequencing (scRNA-seq) and single-cell T cell receptor sequencing (scTCR-seq) analysis, which revealed a proliferative-exhausted MCM FASLGlow CD8 T cell phenotype in severe/critical COVID-19 patients. These CD8 T cells were characterised by G2/M cell cycle arrest, downregulation of respiratory system chain complex genes, and inhibition of mitochondrial biogenesis. CellChat analysis of infected lung epithelial cells and CD8 T cells discovered that the galectin signaling path performed a vital role in CD8 T cell reduction and disorder. To help elucidate the mechanisms, we established SARS-CoV-2 ORF3a-transfected A549 cells, and co-cultured all of them with CD8 T cells for ex vivo experiments. Our results demonstrated that epithelial galectin-3 inhibited the transcription from the mitochondrial respiratory system chain complex III/IV genes of CD8 T cells by suppressing the nuclear translocation of nuclear respiratory system factor 1 (NRF1). Further findings demonstrated the suppression of NRF1 translocation was connected with ERK-related and Akt-related signaling pathways. Importantly, the galectin-3 inhibitor, TD-139, promoted nuclear translocation of NRF1, thus improving the expression from the mitochondrial respiratory system chain complex III/IV genes and also the mitochondrial biogenesis of CD8 T cells. Our study provided new insights in to the immunopathogenesis of COVID-19 and identified potential therapeutic targets for Olitigaltin that treatment and prevention of severe/critical COVID-19 patients.