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

doi:10.1016/j.xcrm.2020.100146

Hydroxychloroquine Inhibits the Trained Innate Immune Response to Interferons

Cell Rep Med. 2020 Nov 10;1(9):100146. doi: 10.1016/j.xcrm.2020.100146. eCollection 2020 Dec 22.

Authors

Nils Rother¹, Cansu Yanginlar¹, Rik G H Lindeboom², Siroon Bekkering³, Mandy M T van Leent^{4

5}, Baranca Buijsers¹, Inge Jonkman¹, Mark de Graaf¹, Marijke Baltissen², Lieke A Lamers², Niels P Riksen³, Zahi A Fayad⁴, Willem J M Mulder^{4

6

7}, Luuk B Hilbrands¹, Leo A B Joosten³, Mihai G Netea^{3

8}, Michiel Vermeulen², Johan van der Vlag¹, Raphaël Duivenvoorden^{1

4}

Affiliations

¹ Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
² Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, Nijmegen, the Netherlands.
³ Department of Internal Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
⁴ Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵ Department of Medical Biochemistry, Amsterdam University Medical Centers, Amsterdam, the Netherlands.
⁶ Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, the Netherlands.
⁷ Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁸ Department of Immunology and Metabolism, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany.

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 Candida, trained innate immunity can be modeled in vitro. 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 in vitro, 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

COVID-19 / immunology
COVID-19 Drug Treatment
Epigenesis, Genetic / drug effects
Humans
Hydroxychloroquine / pharmacology*
Hydroxychloroquine / therapeutic use
Immunity, Innate / drug effects*
Immunologic Memory / drug effects*
Immunomodulation
Interferons / immunology*
Leukocytes, Mononuclear / drug effects
Leukocytes, Mononuclear / immunology
Leukocytes, Mononuclear / metabolism
Lipid Metabolism / drug effects
SARS-CoV-2
Severity of Illness Index

Substances

Hydroxychloroquine
Interferons