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

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.

Mild and Asymptomatic COVID-19 Convalescents Present Long-Term Endotype of Immunosuppression Associated With Neutrophil Subsets Possessing Regulatory Functions

“…In our study, both LDNs/PMN–MDSCs and NDNs were positive for the surface expression of PD–L1, indicating its role in direct cell–to–cell mediated immunosuppression of T–cell response. This, however, does not exclude the involvement of other suppressive–like molecules released by these cell subsets and operating in COVID–19 patients, e.g., arginase–1 or ROS ( 22 , 33 , 85 ). This mechanism could explain a more potent suppressive nature of NDNs despite their generally lower expression of PD–L1, compared to LDNs/PMN–MDSCs.…”

“…The role of myeloid cells with regulatory activity has been indicated in SARS-CoV-2 infection, discriminating between patients with mild and severe disease (23,(32)(33)(34). In particular, LDNs were shown to emerge in severe COVID-19 patients (32), and expansion of PMN-MDSCs with Arg1 activity was associated with an increase of the disease severity (33). The role of Mo-MDSCs, although less frequent, was also documented as related to the course of SARS-CoV-2 infection (34).…”

Myeloid-Derived Suppressor Cells as a Potential Biomarker and Therapeutic Target in COVID-19

“…Finally, reprogramming MDSCs by targeting immunometabolism and epigenetics may also holds promise in resolving lung inflammation associated with COVID-19 (74). As patients with severe COVID-19 have an increased inflammatory response that depletes arginine, and subsequently impairs T cell function, inhibition of arginase-1 and/or replenishment of arginine may be a potential future therapeutic approach in preventing/treating severe COVID-19 (75). Furthermore, the fatty acid transport protein 2 (FATP2), responsible for the uptake of arachidonic acid and for the subsequent synthesis of PGE2 was identified as a regulator of the suppressive functions of PMN-MDSCs (76).…”

Cytokine Overproduction and Immune System Dysregulation in alloHSCT and COVID-19 Patients

“…They produced reactive oxygen species contributing to tissue damage (126) as well as they affect plasma cascades increasing the risk of immunothrombotic clots formation (43). Similarly to the suppressive potential of monocytic-MDSC also granulocytic MDSC may play a role (127). They are released to the periphery 8), (B) Herpes viruses reactivate (CMV reactivation events in post-transplant period) (28,29), in the peripheral blood lymphocytes CD8+CD57+ cells increase (110) -T cell repertoire skewed to highly differentiated T cells effective against chronic infection epitopes but neglecting new challenges, (C) TCR gamma/delta cells reprogrammed by CMV reactivation appear frequently in the blood (prevalence of deltaV2 negative cells) (111), immunodominant clones expand (93).…”

“…They produced reactive oxygen species contributing to tissue damage ( 126 ) as well as they affect plasma cascades increasing the risk of immunothrombotic clots formation ( 43 ). Similarly to the suppressive potential of monocytic-MDSC also granulocytic MDSC may play a role ( 127 ). They are released to the periphery in the course of emergency myelopoiesis driven by the proinflammatory environment and are dysfunctional, and may decrease T cell immune response ( 128 ).…”