Hydroxychloroquine Inhibits the Trained Innate Immune Response to Interferons.

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.

• Authors: 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
• Journal: Cell reports. Medicine (Cell Rep Med) Vol. 1 Issue 9 Pg. 100146 (12 22 2020) ISSN: 2666-3791 [Electronic] United States
• PMID: 33377122 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors.

Chemical References

• Hydroxychloroquine
• Interferons

Topics

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