Limited TCR repertoire and ENTPD1 dysregulation mark late-stage COVID-19

Wang, Na; Vuerich, Marta; Kalbasi, Ahmadreza; Graham, Jonathon J.; Csizmadia, Eva; Manickas Hill, Zachary James; Woolley, Ann; David, Clement; Miller, Eric M.; Gorman, Kara; Hecht, Jonathan L.; Shaefi, Shahzad; Robson, Simon C.; Longhi, Maria Serena

T-cell exhaustion and dysfunction are hallmarks of severe COVID-19. To gain insights into the pathways underlying these alterations, we performed a comprehensive transcriptome analysis of peripheral-blood-mononuclear-cells (PBMCs), spleen, lung, kidney, liver and heart obtained at autopsy from COVID-19 patients and matched controls, using the nCounter-CAR-T-Characterization panel. We found substantial gene alterations in COVID-19-impacted organs, especially the lung where altered TCR repertoires are noted. Reduced TCR repertoires are also observed in PBMCs of severe COVID-19 patients. ENTPD1/CD39, an ectoenzyme defining exhausted T-cells, is upregulated in the lung, liver, spleen and PBMCs of severe COVID-19 patients where expression positively correlates with markers of vasculopathy. Heightened ENTPD1/CD39 is paralleled by elevations in STAT-3 and HIF-1α transcription factors; and by markedly reduced CD39-antisense-RNA, a long-noncoding-RNA negatively regulating ENTPD1/CD39 at the post-transcriptional level. Limited TCR repertoire and aberrant regulation of ENTPD1/CD39 could have permissive roles in COVID-19 progression and indicate potential therapeutic targets to reverse disease.