Transcriptome and Functions of Granulocytic Myeloid-Derived Suppressor Cells Determine their Association with Disease Severity of COVID-19

Matthew J. Dean, LSU Health Sciences Center - New Orleans
Juan B. Ochoa, Ochsner Medical Center - New Orleans
Maria Sanchez-Pino, LSU Health Sciences Center - New Orleans
Jovanny Zabaleta, LSU Health Sciences Center - New Orleans
Jone Garai, LSU Health Sciences Center - New Orleans
Luis Del Valle, LSU Health Sciences Center - New Orleans
Dorota Wyczechowska, LSU Health Sciences Center - New Orleans
Lyndsey Buckner, Ochsner Medical Center - New Orleans
Phaethon Philbrook, LSU Health Sciences Center - New Orleans
Rinku Majumder, LSU Health Sciences Center - New Orleans
Richard Vander Heide, LSU Health Sciences Center - New Orleans
Logan Dunkenberger, LSU Health Sciences Center - New Orleans
Ramesh Thylur, LSU Health Sciences Center - New Orleans
Robert Nossaman, Ochsner Medical Center - New Orleans
W Mark Roberts, Ochsner Medical Center - New Orleans
Andrew Chapple, LSU Health Sciences Center - New Orleans
Jack Collins, Frederick National Laboratory for Cancer Research - Frederick, MD
Brian Luke, Frederick National Laboratory for Cancer Research - Frederick, MD
Randall Johnson, Frederick National Laboratory for Cancer Research - Frederick, MD
Hari Koul, LSU Health Sciences Center - New Orleans
Christopher A. Rees, Boston Children's Hospital - Harvard
Claudia R. Morris, Emory University School of Medicine - Atlanta
Julia Garcia-Diaz, Ochsner Medical Center - New Orleans
Augusto C. Ochoa, LSU Health Sciences Center - New Orleans

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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.