Sars-Cov-2 spike protein and plasma from COVID-19 patients induce extracellular traps by myeloid-derived suppressor cells.

Introduction: Polymorphonuclear-myeloid-derived suppressor cells (PMN-MDSC) are elevated in COVID-19 patients, playing a crucial role in suppressing the SARS-CoV-2 specific T-cell response and serving as an early marker for disease progression. In this study, we investigated the involvement of PMN-MDSC from COVID-19 patients in the formation of extracellular traps (ET). Methods: Fifty RT-PCR-confirmed severe COVID-19 patients admitted to the ICU and ten healthy donors were enrolled. PBMC were isolated from peripheral blood by density gradient centrifugation, and PMN-MDSC frequency was evaluated by flow cytometry. PMN-MDSC were isolated by immunomagnetic separation. ET extrusion was analyzed by immunofluorescence imaging. Apoptosis of pulmonary microvascular endothelial cells cultured with PMN-MDSC was measured by flow cytometry. Results: We found that platelet-rich plasma (PRP) from COVID-19 patients, unlike that from healthy donors, induced ET formation by PMN-MDSC. Furthermore, the PRP-induced ET was found to be independent of Toll-like receptor 4 (TLR4) signaling. Interestingly, the SARS-CoV-2 Spike protein itself can trigger ET formation via a TLR4-dependent pathway. Additionally, PMN-MDSC induced endothelial cell apoptosis through an ET-independent mechanism. Discussion: These findings highlight a previously unrecognized contribution of PMN-MDSCs to the thrombotic complications in severe COVID-19 cases, underscoring their detrimental impact on disease progression.