Aberrant CD39 levels and regulation mark COVID-19 late stage

Abstract Previous studies have reported immune cell exhaustion and perturbed T-cell immunity in novel-coronavirus-disease-19 (COVID-19). Heightened levels of CD39, an ectonucleotidase key to immunoregulation, are detected in CD4 and CD8 T-cells during viral infection where they correlate with worse disease outcome. We performed a comprehensive transcriptome analysis of T-cell related gene pathways in PBMCs from 18 COVID-19 patients (6 convalescent, 6 with moderate disease and 6 with severe disease) and 6 healthy controls (HC); and in formalin-fixed autoptic tissue, obtained from the spleen, lung, kidney, liver and heart of 5 COVID-19 cases and 2 controls. Analysis was performed using nCounter CAR-T characterization panel (NanoString). Our data show that in COVID-19 tissues there is a marked decrease in TCR diversity that is also present in PBMCs of severe patients, when compared with patients with moderate disease, convalescents and HC. A similar pattern is also noted when analyzing PBMCs for TCR signaling, Th1, Th17 and Treg-related transcripts. Heightened CD39 transcripts are detected in lung, liver and spleen of COVID-19 patients as well as in PBMCs obtained from patients with severe disease. A similar trend is observed for STAT-3, and HIF-1alpha, transcription factors that regulate CD39. Notably, CD39-AS RNA, a lncRNA that regulates CD39 at the post-transcriptional level, is markedly reduced in severe COVID-19 patients. In conclusion, our data indicate systemic and local alterations in T-cell immunity in COVID-19. Aberrantly high levels of CD39 and related transcription factors and concomitant decreases in CD39-AS RNA in the late stage of disease suggest a role for CD39 and purinergic signaling in COVID-19 progression.