@article{8f356f9e28f8470ca008fd944fda634d,
title = "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. 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.",
keywords = "COVID-19, SARS-CoV-2, chloroquine, hydroxychloroquine, innate immune memory, interferon, lipidome, monocytes, trained immunity",
author = "Nils Rother and Cansu Yanginlar and Lindeboom, {Rik G.H.} and Siroon Bekkering and {van Leent}, {Mandy M.T.} and Baranca Buijsers and Inge Jonkman and {de Graaf}, Mark and Marijke Baltissen and Lamers, {Lieke A.} and Riksen, {Niels P.} and Fayad, {Zahi A.} and Mulder, {Willem J.M.} and Hilbrands, {Luuk B.} and Joosten, {Leo A.B.} and Netea, {Mihai G.} and Michiel Vermeulen and {van der Vlag}, Johan and Rapha{\"e}l Duivenvoorden",
note = "Funding Information: This work was supported by a Radboudumc Hypatia grant (to R.D.). M.G.N. was supported by an ERC Advanced grant (833247) and a Spinoza grant of the Netherlands Organization for Scientific Research. S.B. is supported by the Dutch Heart Foundation (Dekker grant 2018-T028). The Dutch Kidney Foundation is acknowledged for an innovation grant (16OI11). The Vermeulen lab is part of the Oncode Institute, which is partly funded by the Dutch Cancer Society (KWF). N.R. and R.D. designed the study. N.R. C.Y. R.G.H.L. S.B. M.M.T.v.L. B.B. I.J. M.d.G. M.B. L.A.L. N.P.R. Z.A.F. W.J.M.M. L.B.H. L.A.B.J. M.G.N. M.V. J.v.d.V. and R.D. designed, performed, and oversaw in vitro and ex vivo experiments. N.R. C.Y. B.B. M.d.G. and R.D. collected COVID-19 patient samples. I.J. and R.D. collected and analyzed clinical characteristics of COVID-19 patients. N.R. and R.D. collected and prepared samples for lipidomic analysis. M.B. and L.A.L. prepared samples for and performed RNA and CHIP sequencing. RNA sequencing and ChIP-seq data analysis were performed by R.L. and M.V. S.B. and C.Y. performed and analyzed the flow cytometric study of COVID-19 PBMCs. The manuscript was written by N.R. and R.D. All authors contributed to writing of the manuscript and approved the final draft. R.D. provided funding. The authors declare no competing interests. Funding Information: This work was supported by a Radboudumc Hypatia grant (to R.D.). M.G.N. was supported by an ERC Advanced grant ( 833247 ) and a Spinoza grant of the Netherlands Organization for Scientific Research . S.B. is supported by the Dutch Heart Foundation (Dekker grant 2018-T028 ). The Dutch Kidney Foundation is acknowledged for an innovation grant ( 16OI11 ). The Vermeulen lab is part of the Oncode Institute, which is partly funded by the Dutch Cancer Society (KWF). Publisher Copyright: {\textcopyright} 2020 The Authors",
year = "2020",
month = dec,
day = "22",
doi = "10.1016/j.xcrm.2020.100146",
language = "English",
volume = "1",
journal = "Cell Reports Medicine",
issn = "2666-3791",
publisher = "Cell Press",
number = "9",
}