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

Front Immunol. 2021 Jul 14:12:695972. doi: 10.3389/fimmu.2021.695972. eCollection 2021.

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.

Keywords: COVID-19; G-MDSC; arginase; arginine; coronavirus; interferon; lung injury.

Publication types

  • Observational Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antiviral Agents / administration & dosage
  • Arginase / antagonists & inhibitors
  • Arginase / metabolism
  • Arginine / administration & dosage
  • Arginine / blood
  • Arginine / metabolism
  • Asymptomatic Infections
  • COVID-19 / blood
  • COVID-19 / diagnosis
  • COVID-19 / immunology*
  • COVID-19 Drug Treatment
  • Case-Control Studies
  • Drug Therapy, Combination / methods
  • Enzyme Inhibitors / administration & dosage
  • Female
  • Granulocytes / immunology*
  • Granulocytes / metabolism
  • Healthy Volunteers
  • Humans
  • Interferon Type I / metabolism
  • Male
  • Middle Aged
  • Myeloid-Derived Suppressor Cells / immunology*
  • Myeloid-Derived Suppressor Cells / metabolism
  • SARS-CoV-2 / immunology*
  • Severity of Illness Index
  • Signal Transduction / immunology
  • T-Lymphocytes / immunology

Substances

  • Antiviral Agents
  • Enzyme Inhibitors
  • Interferon Type I
  • Arginine
  • ARG1 protein, human
  • Arginase