ZFIN ID: ZDB-PUB-200304-14
Functional Inhibition of Host Histone Deacetylases (HDACs) Enhances in vitro and in vivo Anti-mycobacterial Activity in Human Macrophages and in Zebrafish
Moreira, J.D., Koch, B.E.V., van Veen, S., Walburg, K.V., Vrieling, F., Mara Pinto Dabés Guimarães, T., Meijer, A.H., Spaink, H.P., Ottenhoff, T.H.M., Haks, M.C., Heemskerk, M.T.
Date: 2020
Source: Frontiers in immunology   11: 36 (Journal)
Registered Authors: Koch, Bjorn, Meijer, Annemarie H., Spaink, Herman P.
Keywords: epigenetic regulation, histone deacetylases (HDAC), host-directed therapy, human macrophages, tuberculosis
MeSH Terms:
  • Animals
  • Antitubercular Agents/administration & dosage*
  • Benzamides/administration & dosage*
  • Blood Donors
  • Cell Survival/drug effects
  • Cells, Cultured
  • Cytokines/metabolism
  • Disease Models, Animal
  • Histone Deacetylase Inhibitors/administration & dosage*
  • Histone Deacetylases/genetics
  • Histone Deacetylases/metabolism*
  • Host-Pathogen Interactions/drug effects*
  • Host-Pathogen Interactions/immunology
  • Humans
  • Hydroxamic Acids/administration & dosage*
  • Macrophages/drug effects
  • Macrophages/enzymology*
  • Macrophages/immunology
  • Macrophages/microbiology*
  • Mycobacterium marinum/drug effects*
  • Mycobacterium tuberculosis/drug effects*
  • Oxadiazoles/administration & dosage*
  • Signal Transduction/drug effects
  • Transcriptome
  • Treatment Outcome
  • Tuberculosis/drug therapy*
  • Tuberculosis/immunology
  • Tuberculosis/metabolism
  • Tuberculosis/microbiology
  • Zebrafish/embryology
  • Zebrafish/immunology
  • Zebrafish/metabolism*
  • Zebrafish/microbiology*
PubMed: 32117228 Full text @ Front Immunol
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ABSTRACT
The rapid and persistent increase of drug-resistant Mycobacterium tuberculosis (Mtb) infections poses increasing global problems in combatting tuberculosis (TB), prompting for the development of alternative strategies including host-directed therapy (HDT). Since Mtb is an intracellular pathogen with a remarkable ability to manipulate host intracellular signaling pathways to escape from host defense, pharmacological reprogramming of the immune system represents a novel, potentially powerful therapeutic strategy that should be effective also against drug-resistant Mtb. Here, we found that host-pathogen interactions in Mtb-infected primary human macrophages affected host epigenetic features by modifying histone deacetylase (HDAC) transcriptomic levels. In addition, broad spectrum inhibition of HDACs enhanced the antimicrobial response of both pro-inflammatory macrophages (Mϕ1) and anti-inflammatory macrophages (Mϕ2), while selective inhibition of class IIa HDACs mainly decreased bacterial outgrowth in Mϕ2. Moreover, chemical inhibition of HDAC activity during differentiation polarized macrophages into a more bactericidal phenotype with a concomitant decrease in the secretion levels of inflammatory cytokines. Importantly, in vivo chemical inhibition of HDAC activity in Mycobacterium marinum-infected zebrafish embryos, a well-characterized animal model for tuberculosis, significantly reduced mycobacterial burden, validating our in vitro findings in primary human macrophages. Collectively, these data identify HDACs as druggable host targets for HDT against intracellular Mtb.
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