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

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

doi:10.1016/j.isci.2021.103205

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

iScience. 2021 Oct 22;24(10):103205. doi: 10.1016/j.isci.2021.103205. Epub 2021 Sep 30.

Authors

Na Wang^{1

2

3}, Marta Vuerich¹, Ahmadreza Kalbasi¹, Jonathon J Graham¹, Eva Csizmadia¹, Zachary James Manickas-Hill⁴, Ann Woolley⁵, Clement David⁶, Eric M Miller⁶, Kara Gorman⁶, Jonathan L Hecht⁷, Shahzad Shaefi¹, Simon C Robson^{1

8}, Maria Serena Longhi¹

Affiliations

¹ Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
² Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jingwu Road, Jinan, Shandong 250021, China.
³ School of Medicine, Shandong University, 44 Wenhuaxilu, Jinan, Shandong 250021, China.
⁴ Ragon Institute of MGH, MIT and Harvard, 400 Technology Square, Cambridge, MA 02139, USA.
⁵ Division of Infectious Diseases, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.
⁶ NanoString Technologies, 530 Fairview Avenue N, Seattle, WA 98109, USA.
⁷ Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
⁸ Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.

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: Immunology; Virology.

Abstract

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