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

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.

The mechanism underlying extrapulmonary complications of the coronavirus disease 2019 and its therapeutic implication

“…127 , 128 The circulating granulocyte-myeloid-derived suppressor cells (G-MDSC) expressing high levels of arginase-1(Arg1) increased significantly in COVID-19 patients, which can deplete arginine in the plasma and inhibit T-cell receptor signal transduction, thereby leading to T-cell dysfunction, also impairing the production of nitric oxide and increasing endothelial cell dysfunction, and promoting intravascular coagulation. 129 Moreover, due to sustained immune activation during COVID-19 convalescence, activated and infected endothelial cells may be susceptible to direct T-cell-mediated cytotoxicity that may intensify endothelial dysfunction in patients with COVID-19. 130…”

Targeting Arginine in COVID-19-Induced Immunopathology and Vasculopathy

“…Monocytic MDSC growth is strikingly associated with COVID-19 disease severity and purified MDSCs block T cell proliferation, in part, via an ARG1-dependent mechanism, supporting a role for these cells in the aberrant COVID-19 immune response [ 19 ]. Moreover, granulocytic MDSCs express and secrete high levels of ARG1 protein that effectively depletes arginine from the local environment [ 136 ]. In fact, the expansion of MDSCs contributes to platelet activation by arginine deprivation during SARS-CoV-2 infection [ 137 ].…”

Virus-Induced Membrane Fusion in Neurodegenerative Disorders

“…These contradictory findings can be reconciled to some extent as arginine may be both helpful and detrimental depending on the amount of arginase expression. Increased arginase depletes both arginine and NO, predisposing to COVID-19 critical illness and neurodegeneration ( Derakhshani et al., 2021 ; Dean et al., 2021 ). Therefore, patients with elevated arginase levels, would likely benefit from NO supplementation (but not arginine as this may upregulate the ornithine/urea pathway) ( Lotz et al., 2021 ; Fang et al., 2021 ).…”