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
  • 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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