Journal
CELL REPORTS MEDICINE
Volume 1, Issue 9, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.xcrm.2020.100146
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Funding
- Radboudumc Hypatia grant
- ERC Advanced grant [833247]
- Spinoza grant of the Netherlands Organization for Scientific Research
- Dutch Heart Foundation [2018-T028]
- Dutch Kidney Foundation [16OI11]
- Dutch Cancer Society (KWF)
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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.
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