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 Nossaman, W Mark Roberts, Andrew G Chapple, Jiande Wu, Chindo Hicks, Jack Collins, Brian Luke, Randall Johnson, Hari K Koul, Chris A Rees, Claudia R Morris, Julia Garcia-Diaz, Augusto C Ochoa
Author Information
Matthew J Dean: Louisiana State University Cancer Center, New Orleans, LA, United States.
Juan B Ochoa: Department of Surgery, Ochsner Medical Center, New Orleans, LA, United States.
Maria Dulfary Sanchez-Pino: Louisiana State University Cancer Center, New Orleans, LA, United States.
Jovanny Zabaleta: Louisiana State University Cancer Center, New Orleans, LA, United States.
Jone Garai: Louisiana State University Cancer Center, New Orleans, LA, United States.
Luis Del Valle: Louisiana State University Cancer Center, New Orleans, LA, United States.
Dorota Wyczechowska: Louisiana State University Cancer Center, New Orleans, LA, United States.
Lyndsey Buckner Baiamonte: Tissue Biorepository, Ochsner Medical Center, New Orleans, LA, United States.
Phaethon Philbrook: Louisiana State University Cancer Center, New Orleans, LA, United States.
Rinku Majumder: Department of Biochemistry, LSU Health, New Orleans, LA, United States.
Richard S Vander Heide: Department of Pathology LSU Health, New Orleans, LA, United States.
Logan Dunkenberger: Louisiana State University Cancer Center, New Orleans, LA, United States.
Ramesh Puttalingaiah Thylur: Louisiana State University Cancer Center, New Orleans, LA, United States.
Bobby Nossaman: Department of Surgery, Ochsner Medical Center, New Orleans, LA, United States.
W Mark Roberts: Department of Internal Medicine, Ochsner Medical Center, New Orleans, LA, United States.
Andrew G Chapple: Louisiana State University Cancer Center, New Orleans, LA, United States.
Jiande Wu: Department of Genetics, LSU Health, New Orleans, LA, United States.
Chindo Hicks: Department of Genetics, LSU Health, New Orleans, LA, United States.
Jack Collins: Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD, United States.
Brian Luke: Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD, United States.
Randall Johnson: Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD, United States.
Hari K Koul: Louisiana State University Cancer Center, New Orleans, LA, United States.
Chris A Rees: Division of Emergency Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA, United States.
Claudia R Morris: Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, Children's Healthcare of Atlanta, Atlanta, GA, United States.
Julia Garcia-Diaz: Tissue Biorepository, Ochsner Medical Center, New Orleans, LA, United States.
Augusto C Ochoa: Louisiana State University Cancer Center, New Orleans, LA, United States.
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 (ArgG-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 ArgG-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.
