Severe COVID-19 Is Characterized by an Impaired Type I Interferon Response and Elevated Levels of Arginase Producing Granulocytic Myeloid Derived Suppressor Cells
Matthew J. Dean, Juan B. Ochoa, Maria Dulfary Sanchez‐Pino, Jovanny Zabaleta, Jone Garai, Luis Del Valle, Dorota Wyczechowska, Lyndsey Buckner Baiamonte, Phaethon Philbrook, Rinku Majumder, Richard S. Vander Heide, Logan Dunkenberger, Ramesh Puttalingaiah Thylur, Bobby D. Nossaman, W. Mark Roberts, Andrew Chapple, Wu Jiande, Chindo Hicks, Jack Collins, Brian T. Luke, Randall C. Johnson, Hari K. Koul, Chris A. Rees, Claudia R. Morris, Julia Garcia‐Diaz, Augusto C. Ochoa
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.