tetano
Editor, Senior Moderator
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[SUP] 1 [/SUP], Cansu Yanginlar[SUP] 1 [/SUP], Rik G H Lindeboom[SUP] 2 [/SUP], Siroon Bekkering[SUP] 3 [/SUP], Mandy M T van Leent[SUP] 4 5 [/SUP], Baranca Buijsers[SUP] 1 [/SUP], Inge Jonkman[SUP] 1 [/SUP], Mark de Graaf[SUP] 1 [/SUP], Marijke Baltissen[SUP] 2 [/SUP], Lieke A Lamers[SUP] 2 [/SUP], Niels P Riksen[SUP] 3 [/SUP], Zahi A Fayad[SUP] 4 [/SUP], Willem J M Mulder[SUP] 4 6 7 [/SUP], Luuk B Hilbrands[SUP] 1 [/SUP], Leo A B Joosten[SUP] 3 [/SUP], Mihai G Netea[SUP] 3 8 [/SUP], Michiel Vermeulen[SUP] 2 [/SUP], Johan van der Vlag[SUP] 1 [/SUP], Rapha?l Duivenvoorden[SUP] 1 4 [/SUP]
Affiliations
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.
. 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[SUP] 1 [/SUP], Cansu Yanginlar[SUP] 1 [/SUP], Rik G H Lindeboom[SUP] 2 [/SUP], Siroon Bekkering[SUP] 3 [/SUP], Mandy M T van Leent[SUP] 4 5 [/SUP], Baranca Buijsers[SUP] 1 [/SUP], Inge Jonkman[SUP] 1 [/SUP], Mark de Graaf[SUP] 1 [/SUP], Marijke Baltissen[SUP] 2 [/SUP], Lieke A Lamers[SUP] 2 [/SUP], Niels P Riksen[SUP] 3 [/SUP], Zahi A Fayad[SUP] 4 [/SUP], Willem J M Mulder[SUP] 4 6 7 [/SUP], Luuk B Hilbrands[SUP] 1 [/SUP], Leo A B Joosten[SUP] 3 [/SUP], Mihai G Netea[SUP] 3 8 [/SUP], Michiel Vermeulen[SUP] 2 [/SUP], Johan van der Vlag[SUP] 1 [/SUP], Rapha?l Duivenvoorden[SUP] 1 4 [/SUP]
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.