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This study demonstrates that patients hospitalized with COVID-19 show evidence of neutrophil degranulation and have increased expression of neutrophil surface lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), a marker of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Both early LOX-1 and programmed death-ligand 1 (PD-L1) expression on neutrophils were associated with development of severe disease. To determine whether tissue damage or inflammation is required to induce PMN-MDSCs or whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly activates neutrophils to become PMN-MDSCs, we incubated healthy human neutrophils with SARS-CoV-2. SARS-CoV-2 rapidly induced LOX-1 surface expression in healthy neutrophils independent of productive infection. LOX-1 induction was dependent on granule exocytosis and promoted up-regulation of reactive oxygen species, CD63, and PD-L1, enabling LOX-1\n                    <jats:sup>+<\/jats:sup>\n                    neutrophils to suppress autologous T cell proliferation in vitro. These results support a role for PMN-MDSCs in mediating severe COVID-19, and inhibition of PD-L1 represents a potential therapeutic strategy for enhancing the immune response in acute SARS-CoV-2 infection.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adn7527","type":"journal-article","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T14:00:24Z","timestamp":1747836024000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":15,"title":["SARS-CoV-2 induces neutrophil degranulation and differentiation into myeloid-derived suppressor cells associated with severe COVID-19"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6920-7718","authenticated-orcid":true,"given":"Leon L.","family":"Hsieh","sequence":"first","affiliation":[{"name":"Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA."},{"name":"W. 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