2. Academic Validation
  3. SARS-CoV-2 induces neutrophil degranulation and differentiation into myeloid-derived suppressor cells associated with severe COVID-19

SARS-CoV-2 induces neutrophil degranulation and differentiation into myeloid-derived suppressor cells associated with severe COVID-19

  • Sci Transl Med. 2025 May 21;17(799):eadn7527. doi: 10.1126/scitranslmed.adn7527.
Leon L Hsieh 1 2,  Elizabeth A Thompson 2,  Nirvani P Jairam 1,  Katerina Roznik 1 2,  Alexis Figueroa 1,  Tihitina Aytenfisu 1,  Weiqiang Zhou 3,  Naina Gour 4,  Kuan-Hao Chao 5,  Aaron M Milstone 6,  Emily Egbert 6,  Franco D'Alessio 1,  Petros C Karakousis 1 2 7,  Alvaro Ordoñez 6,  Eileen P Scully 1,  Andrew Pekosz 2,  Andrew H Karaba 1,  Andrea L Cox 1 2 8
Affiliations

Affiliations

  • 1 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • 2 W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA.
  • 3 Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA.
  • 4 Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • 5 Center for Computational Biology, Johns Hopkins University, Baltimore, MD 21287, USA.
  • 6 Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • 7 Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21287, USA.
  • 8 Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
PMID: 40397714 DOI: 10.1126/scitranslmed.adn7527
Abstract

Severe COVID-19 presents with a distinct immunological profile, characterized by elevated neutrophil and reduced lymphocyte counts, seen commonly in Fungal and Bacterial infections. 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+ 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.

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