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.
Highlights
COVID-19 disease ranges from asymptomatic (35% of cases) to severe requiring treatment in intensive care units
NOX-1 and NOX-2 enzymes catalyze the synthesis of reactive oxygen species (ROS). These results suggest that the massive infiltration of the lungs by Arg+G-MDSC simultaneously expressing NOX1/2, may inhibit T cells and cause endothelial cell dysfunction, and directly damage alveolar epithelium through the release of ROS
The complete lists of differentially expressed genes are included in Supplemental Table 2. These data demonstrate the importance of Arg+G-MDSC in the pathophysiology of severe COVID-19
Summary
COVID-19 disease ranges from asymptomatic (35% of cases) to severe requiring treatment in intensive care units (https://www. cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidancemanagement-patients.html). Rees et al [12] have reported alterations in amino acid levels, including arginine and ornithine, in COVID-19 patients Another recent paper has described increased RNA expression of Arg in the peripheral blood mononuclear cells of COVID-19 patients, they did not identify the cell of origin of this Arg1 [13]. RNAseq studies demonstrated contrasting transcriptomes, where G-MDSC from asymptomatic COVID-19 patients had increased expression of type I IFN genes and pathways, while GMDSC from severe COVID-19 patients had instead increased expression of genes associated with granulocyte functions and degranulation. These data support the concept that Arg+GMDSC may play a significant role in the pathophysiology of COVID-19
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