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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: Rother N, Yanginlar C, Lindeboom RGH, Bekkering S, van Leent MMT, Buijsers B, Jonkman I, de Graaf M, Baltissen M, Lamers LA, Riksen NP, Fayad ZA, Mulder WJM, Hilbrands LB, Joosten LAB, Netea MG, Vermeulen M, van der Vlag J, Duivenvoorden R.
Journal: Cell Rep Med. 2020 Nov 10;1(9):100146
Year: 2020
PubMed: PMID: 33377122 (Go to PubMed)