Severe COVID-19 Is Characterized by an Impaired Type I Interferon Response and Elevated Levels of Arginase Producing Granulocytic Myeloid Derived Suppressor Cells

  1. Matthew J. Dean
  2. Juan B. Ochoa
  3. Maria Dulfary Sanchez-Pino
  4. Jovanny Zabaleta
  5. Jone Garai
  6. Luis Del Valle
  7. Dorota Wyczechowska
  8. Lyndsey Buckner Baiamonte
  9. Phaethon Philbrook
  10. Rinku Majumder
  11. Richard S. Vander Heide
  12. Logan Dunkenberger
  13. Ramesh Puttalingaiah Thylur
  14. Bobby Nossaman
  15. W. Mark Roberts
  16. Andrew G. Chapple
  17. Jiande Wu
  18. Chindo Hicks
  19. Jack Collins
  20. Brian Luke
  21. Randall Johnson
  22. Hari K. Koul
  23. Chris A. Rees
  24. Claudia R. Morris
  25. Julia Garcia-Diaz
  26. Augusto C. Ochoa

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Abstract

COVID-19 ranges from asymptomatic in 35% of cases to severe in 20% of patients. Differences in the type and degree of inflammation appear to determine the severity of the disease. Recent reports show an increase in circulating monocytic-myeloid-derived suppressor cells (M-MDSC) in severe COVID 19 that deplete arginine but are not associated with respiratory complications. Our data shows that differences in the type, function and transcriptome of granulocytic-MDSC (G-MDSC) may in part explain the severity COVID-19, in particular the association with pulmonary complications. Large infiltrates by Arginase 1 + G-MDSC (Arg + G-MDSC), expressing NOX-1 and NOX-2 (important for production of reactive oxygen species) were found in the lungs of patients who died from COVID-19 complications. Increased circulating Arg + G-MDSC depleted arginine, which impaired T cell receptor and endothelial cell function. Transcriptomic signatures of G-MDSC from patients with different stages of COVID-19, revealed that asymptomatic patients had increased expression of pathways and genes associated with type I interferon (IFN), while patients with severe COVID-19 had increased expression of genes associated with arginase production, and granulocyte degranulation and function. These results suggest that asymptomatic patients develop a protective type I IFN response, while patients with severe COVID-19 have an increased inflammatory response that depletes arginine, impairs T cell and endothelial cell function, and causes extensive pulmonary damage. Therefore, inhibition of arginase-1 and/or replenishment of arginine may be important in preventing/treating severe COVID-19.

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  1. Version published to 10.3389/fimmu.2021.695972
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    SciScore for 10.1101/2021.03.26.21254441: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    No key resources detected.

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
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    • Thank you for including a protocol registration statement.

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  3. Version published to 10.1101/2021.03.26.21254441v1 on medRxiv