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
Affiliations
Na Wang
Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA; Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jingwu Road, Jinan, Shandong 250021, China; School of Medicine, Shandong University, 44 Wenhuaxilu, Jinan, Shandong 250021, China
Marta Vuerich
Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA
Ahmadreza Kalbasi
Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA
Jonathon J. Graham
Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA
Eva Csizmadia
Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA
Zachary James Manickas-Hill
Ragon Institute of MGH, MIT and Harvard, 400 Technology Square, Cambridge, MA 02139, USA
Ann Woolley
Division of Infectious Diseases, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA
Clement David
NanoString Technologies, 530 Fairview Avenue N, Seattle, WA 98109, USA
Eric M. Miller
NanoString Technologies, 530 Fairview Avenue N, Seattle, WA 98109, USA
Kara Gorman
NanoString Technologies, 530 Fairview Avenue N, Seattle, WA 98109, USA
Jonathan L. Hecht
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA
Shahzad Shaefi
Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA
Simon C. Robson
Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA; Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA
Maria Serena Longhi
Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA; Corresponding author
Summary: 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.
