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Cell reports. Medicine
12 22, 2020;1 (9): 100146.

Hydroxychloroquine Inhibits the Trained Innate Immune Response to Interferons.

Nils Rother, Cansu Yanginlar, Rik G H Lindeboom, Siroon Bekkering, Mandy M T van Leent, Baranca Buijsers, Inge Jonkman, Mark de Graaf, Marijke Baltissen, Lieke A Lamers, Niels P Riksen, Zahi A Fayad, Willem J M Mulder, Luuk B Hilbrands, Leo A B Joosten, Mihai G Netea, Michiel Vermeulen, Johan van der Vlag, Raphaël Duivenvoorden
Author Information
  1. Nils Rother: Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
  2. Cansu Yanginlar: Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
  3. Rik G H Lindeboom: Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, Nijmegen, the Netherlands.
  4. Siroon Bekkering: Department of Internal Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
  5. Mandy M T van Leent: Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  6. Baranca Buijsers: Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
  7. Inge Jonkman: Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
  8. Mark de Graaf: Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
  9. Marijke Baltissen: Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, Nijmegen, the Netherlands.
  10. Lieke A Lamers: Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, Nijmegen, the Netherlands.
  11. Niels P Riksen: Department of Internal Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
  12. Zahi A Fayad: Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  13. Willem J M Mulder: Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  14. Luuk B Hilbrands: Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
  15. Leo A B Joosten: Department of Internal Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
  16. Mihai G Netea: Department of Internal Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
  17. Michiel Vermeulen: Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, Nijmegen, the Netherlands.
  18. Johan van der Vlag: Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
  19. Raphaël Duivenvoorden: Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
PMID: 33377122 DOI: 10.1016/j.xcrm.2020.100146

Abstract

Hydroxychloroquine is being investigated for a potential prophylactic effect in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but its mechanism of action is poorly understood. Circulating leukocytes from the blood of coronavirus disease 2019 (COVID-19) patients show increased responses to Toll-like receptor ligands, suggestive of trained immunity. By analyzing interferon responses of peripheral blood mononuclear cells from healthy donors conditioned with heat-killed , trained innate immunity can be modeled . In this model, hydroxychloroquine inhibits the responsiveness of these innate immune cells to virus-like stimuli and interferons. This is associated with a suppression of histone 3 lysine 27 acetylation and histone 3 lysine 4 trimethylation of inflammation-related genes, changes in the cellular lipidome, and decreased expression of interferon-stimulated genes. Our findings indicate that hydroxychloroquine inhibits trained immunity , which may not be beneficial for the antiviral innate immune response to SARS-CoV-2 infection in patients.

Keywords

COVID-19 SARS-CoV-2 chloroquine hydroxychloroquine innate immune memory interferon lipidome monocytes trained immunity

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MeSH Term

COVID-19
Epigenesis, Genetic
Humans
Hydroxychloroquine
Immunity, Innate
Immunologic Memory
Immunomodulation
Interferons
Leukocytes, Mononuclear
Lipid Metabolism
SARS-CoV-2
Severity of Illness Index
COVID-19 Drug Treatment

Chemicals

Hydroxychloroquine
Interferons
Journal Article Research Support, Non-U.S. Gov't

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