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 (Corresponding author)

Research output: Contribution to journalArticleAcademicpeer-review

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. Peripheral blood mononuclear cells (PBMCs) of COVID-19 patients show increased responses to Toll-like receptor ligands, suggestive of innate immune reprogramming. Rother et al. show that hydroxychloroquine inhibits the interferon response of Candida-trained PBMCs from healthy donors in vitro and blocks associated changes in lipidome and histone modifications.

Original languageEnglish
Article number100146
Number of pages20
JournalCell Reports. Medicine
Volume1
Issue number9
DOIs
Publication statusPublished - 22 Dec 2020

Keywords

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

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