AUTHOR=Dean Matthew J. , Ochoa Juan B. , Sanchez-Pino Maria Dulfary , Zabaleta Jovanny , Garai Jone , Del Valle Luis , Wyczechowska Dorota , Baiamonte Lyndsey Buckner , Philbrook Phaethon , Majumder Rinku , Vander Heide Richard S. , Dunkenberger Logan , Thylur Ramesh Puttalingaiah , Nossaman Bobby , Roberts W. Mark , Chapple Andrew G. , Wu Jiande , Hicks Chindo , Collins Jack , Luke Brian , Johnson Randall , Koul Hari K. , Rees Chris A. , Morris Claudia R. , Garcia-Diaz Julia , Ochoa Augusto C. TITLE=Severe COVID-19 Is Characterized by an Impaired Type I Interferon Response and Elevated Levels of Arginase Producing Granulocytic Myeloid Derived Suppressor Cells JOURNAL=Frontiers in Immunology VOLUME=12 YEAR=2021 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.695972 DOI=10.3389/fimmu.2021.695972 ISSN=1664-3224 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.