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Cell Rep Med
. 2020 Nov 10;1(9):100146.
doi: 10.1016/j.xcrm.2020.100146. eCollection 2020 Dec 22.
Hydroxychloroquine Inhibits the Trained Innate Immune Response to Interferons
Nils Rother 1 , Cansu Yanginlar 1 , Rik G H Lindeboom 2 , Siroon Bekkering 3 , Mandy M T van Leent 4 5 , Baranca Buijsers 1 , Inge Jonkman 1 , Mark de Graaf 1 , Marijke Baltissen 2 , Lieke A Lamers 2 , Niels P Riksen 3 , Zahi A Fayad 4 , Willem J M Mulder 4 6 7 , Luuk B Hilbrands 1 , Leo A B Joosten 3 , Mihai G Netea 3 8 , Michiel Vermeulen 2 , Johan van der Vlag 1 , Rapha?l Duivenvoorden 1 4
Affiliations
- PMID: 33377122
- PMCID: PMC7762774
- 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 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.