tetano
Editor, Senior Moderator
iScience
. 2021 Sep 30;103205.
doi: 10.1016/j.isci.2021.103205. Online ahead of print.
Limited TCR repertoire and ENTPD1 dysregulation mark late-stage COVID-19
Na Wang[SUP] 1 2 3 [/SUP], Marta Vuerich[SUP] 1 [/SUP], Ahmadreza Kalbasi[SUP] 1 [/SUP], Jonathon J Graham[SUP] 1 [/SUP], Eva Csizmadia[SUP] 1 [/SUP], Zachary James Manickas Hill[SUP] 4 [/SUP], Ann Woolley[SUP] 5 [/SUP], Clement David[SUP] 6 [/SUP], Eric M Miller[SUP] 6 [/SUP], Kara Gorman[SUP] 6 [/SUP], Jonathan L Hecht[SUP] 7 [/SUP], Shahzad Shaefi[SUP] 1 [/SUP], Simon C Robson[SUP] 1 8 [/SUP], Maria Serena Longhi[SUP] 1 [/SUP]
Affiliations
Abstract
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.
Keywords: AHR, aryl hydrocarbon receptor; COVID-19, coronavirus-disease-19; DEG, differentially expressed genes; FFPE, formalin fixed paraffin embedded; GSEA, gene set enrichment analysis; HIF-1α, hypoxia inducible factor 1-alpha; PBMCs, peripheral blood mononuclear cells; PPI, protein-protein interaction; SARS-CoV-2; SARS-CoV-2, severe-acute-respiratory-syndrome-coronavirus-2; STAT-3, signal transducer and activator of transcription-3; T-cell-receptor; TCR, T-cell receptor; ectonucleotidase; immune exhaustion.
. 2021 Sep 30;103205.
doi: 10.1016/j.isci.2021.103205. Online ahead of print.
Limited TCR repertoire and ENTPD1 dysregulation mark late-stage COVID-19
Na Wang[SUP] 1 2 3 [/SUP], Marta Vuerich[SUP] 1 [/SUP], Ahmadreza Kalbasi[SUP] 1 [/SUP], Jonathon J Graham[SUP] 1 [/SUP], Eva Csizmadia[SUP] 1 [/SUP], Zachary James Manickas Hill[SUP] 4 [/SUP], Ann Woolley[SUP] 5 [/SUP], Clement David[SUP] 6 [/SUP], Eric M Miller[SUP] 6 [/SUP], Kara Gorman[SUP] 6 [/SUP], Jonathan L Hecht[SUP] 7 [/SUP], Shahzad Shaefi[SUP] 1 [/SUP], Simon C Robson[SUP] 1 8 [/SUP], Maria Serena Longhi[SUP] 1 [/SUP]
Affiliations
- PMID: 34608452
- PMCID: PMC8482538
- DOI: 10.1016/j.isci.2021.103205
Abstract
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.
Keywords: AHR, aryl hydrocarbon receptor; COVID-19, coronavirus-disease-19; DEG, differentially expressed genes; FFPE, formalin fixed paraffin embedded; GSEA, gene set enrichment analysis; HIF-1α, hypoxia inducible factor 1-alpha; PBMCs, peripheral blood mononuclear cells; PPI, protein-protein interaction; SARS-CoV-2; SARS-CoV-2, severe-acute-respiratory-syndrome-coronavirus-2; STAT-3, signal transducer and activator of transcription-3; T-cell-receptor; TCR, T-cell receptor; ectonucleotidase; immune exhaustion.