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

• Type of Material: Article
• Authors: Matthew J. Dean, Louisiana State University; Juan B. Ochoa, Ochsner Medical Center; Maria Dulfary Sanchez-Pino, Louisiana State University; Jovanny Zabaleta, Louisiana State University; Jone Garai, Louisiana State University; Luis Del Valle, Louisiana State University; Dorota Wyczechowska, Louisiana State University; Lyndsey Baiamonte, Ochsner Medical Center; Phaethon Philbrook, Louisiana State University; Rinku Majumder, Louisiana State University; Richard S. Vander Heide, Louisiana State University; Logan Dunkenberger, Louisiana State University; Ramesh Puttalingaiah Thylur, Louisiana State University; Bobby Nossaman, Ochsner Medical Center; W. Mark Roberts, Ochsner Medical Center; Andrew G. Chapple, Louisiana State University; Jiande Wu, Louisiana State University; Chindo Hicks, Louisiana State University; Jack Collins, Frederick National Laboratory for Cancer Research; Brian Luke, Frederick National Laboratory for Cancer Research; Randall Johnson, Frederick National Laboratory for Cancer Research; Hari K. Koul, Louisiana State University; Chris A. Rees, Boston Children's Hospital; Claudia Morris, Emory University; Julia Garcia-Diaz, Ochsner Medical Center; Augusto C. Ochoa, Louisiana State University
• Language: English
• Date: 2021-07-14
• Publisher: FRONTIERS MEDIA SA
• Publication Version: Final Published Version
• Copyright Statement: © 2021 Dean, Ochoa, Sanchez-Pino, Zabaleta, Garai, Del Valle, Wyczechowska, Baiamonte, Philbrook, Majumder, Vander Heide, Dunkenberger, Thylur, Nossaman, Roberts, Chapple, Wu, Hicks, Collins, Luke, Johnson, Koul, Rees, Morris, Garcia-Diaz and Ochoa
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3389/fimmu.2021.695972
• Title of Journal or Parent Work: FRONTIERS IN IMMUNOLOGY
• Volume: 12
• Start Page: 695972
• End Page: 695972
• Grant/Funding Information: This project was supported by funding from LSU Health and Ochsner Medical Center. Core facilities, personnel and services partially supported by an internal LSU Health COVID-19 grant as well as P20-GM103501, P20-CA233374, P20-GM121288, and U54-GM104940. This project has been funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
• Keywords: G-MDSC; coronavirus; Immunology; ARGININE; arginine; COVID-19; Life Sciences & Biomedicine; interferon; HEALTH; arginase; T-CELLS; ENDOTHELIAL DYSFUNCTION; EXPRESSION; Science & Technology; lung injury
• Research Categories: Biology, Cell; Health Sciences, Immunology

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.