Functional Inhibition of Host Histone Deacetylases (HDACs) Enhances in vitro and in vivo Anti-mycobacterial Activity in Human Macrophages and in Zebrafish.

Herman P Spaink,Tom H M Ottenhoff,Jôsimar D Moreira,Annemarie H Meijer,Frank Vrieling,Matthias T Heemskerk,Mariëlle C Haks,Suzanne Van Veen,Kimberley V Walburg,Bjørn E V Koch,Tânia Mara Pinto Dabés Guimarães

doi:10.3389/fimmu.2020.00036

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.

Highlights

Tuberculosis (TB) is a health threat of global dimensions, and is caused by the highly successful human pathogen Mycobacterium tuberculosis (Mtb)
To explore whether intracellular survival of Mtb is controlled by host epigenetic features, we investigated whether MtbH37Rv (Mtb) infection could impact histone acetylation in primary human pro-inflammatory (Mφ1) and anti-inflammatory (Mφ2) macrophages, representing opposing ends of the macrophage differentiation spectrum
We report that histone deacetylase (HDAC) transcriptomic levels are strongly affected by Mtb-infection in primary human macrophages

Summary

Introduction

Tuberculosis (TB) is a health threat of global dimensions, and is caused by the highly successful human pathogen Mycobacterium tuberculosis (Mtb). Together with the rising frequency of multi-, extensively-, and even totally drug-resistant (MDR/XDR/TDR) Mtb strains, and the fact that many druggable targets in pathogens are already inhibited by current antibiotics [2], it is crucial to develop new and much more effective strategies that act by mechanisms different from those already targeted by current interventions. Since Mtb has a remarkable ability to manipulate intracellular signaling pathways which promote its escape from host defense in human cells, host-directed therapies (HDT) would represent a therapeutic strategy that would be effective against currently untreatable strains since these compounds act on host and not on pathogen molecules

Methods

Results

Conclusion