Hydroxychloroquine Inhibits the Trained Innate Immune Response to Interferons

Cell Rep Med. 2020 Nov 10;1(9):100146. doi: 10.1016/j.xcrm.2020.100146. eCollection 2020 Dec 22.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • COVID-19 / drug therapy
  • COVID-19 / immunology
  • Epigenesis, Genetic / drug effects
  • Humans
  • Hydroxychloroquine / pharmacology*
  • Hydroxychloroquine / therapeutic use
  • Immunity, Innate / drug effects*
  • Immunologic Memory / drug effects*
  • Immunomodulation
  • Interferons / immunology*
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / immunology
  • Leukocytes, Mononuclear / metabolism
  • Lipid Metabolism / drug effects
  • SARS-CoV-2
  • Severity of Illness Index


  • Hydroxychloroquine
  • Interferons

Supplementary concepts

  • COVID-19 drug treatment