期刊
FRONTIERS IN IMMUNOLOGY
卷 11, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2020.00036
关键词
tuberculosis; host-directed therapy; epigenetic regulation; histone deacetylases (HDAC); human macrophages
类别
资金
- Netherlands Organization for Health Research and Development (ZonMw-TOP grant) [91214038]
- NWO Domain Applied and Engineering Sciences (NWO-TTW grant) [13259]
- Brazilian Federal Agency for Support and Evaluation of Graduate Education (CAPES)
- EU-ToxRisk project (An Integrated European Flagship Program Driving Mechanism-Based Toxicity Testing and Risk Assessment for the twenty first century) - European Commission under the Horizon 2020 program [681002]
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 (M phi 1) and anti-inflammatory macrophages (M phi 2), while selective inhibition of class IIa HDACs mainly decreased bacterial outgrowth in M phi 2. 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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