Hydroxychloroquine Inhibits the Trained Innate Immune Response to Interferons

Rother, Nils; Yanginlar, Cansu; Lindeboom, Rik G.H.; Bekkering, Siroon; van Leent, Mandy M.T.; Buijsers, Baranca; Jonkman, Inge; de Graaf, Mark; Baltissen, Marijke; Lamers, Lieke A.; Riksen, Niels P.; Fayad, Zahi A.; Mulder, Willem J.M.; Hilbrands, Luuk B.; Joosten, Leo A.B.; Netea, Mihai G.; Vermeulen, Michiel; van der Vlag, Johan; Duivenvoorden, Raphaël

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.