AUTHOR=van Doorn Cassandra L. R. , Steenbergen Sanne A. M. , Walburg Kimberley V. , Ottenhoff Tom H. M. 

TITLE=Pharmacological Poly (ADP-Ribose) Polymerase Inhibitors Decrease Mycobacterium tuberculosis Survival in Human Macrophages

JOURNAL=Frontiers in Immunology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.712021

DOI=10.3389/fimmu.2021.712021

ISSN=1664-3224

ABSTRACT=<p>Diabetes mellites (DM) is correlated with increased susceptibility to and disease progression of tuberculosis (TB), and strongly impairs effective global TB control measures. To better control the TB-DM co-epidemic, unravelling the bidirectional interactivity between DM-associated molecular processes and immune responses to <italic>Mycobacterium tuberculosis</italic> (<italic>Mtb)</italic> is urgently required. Since poly (ADP-ribose) polymerase (PARP) activation has been associated with DM and with <italic>Mtb</italic> infection in mouse models, we have investigated whether PARP inhibition by pharmacological compounds can interfere with host protection against <italic>Mtb</italic> in human macrophage subsets, the predominant target cell of <italic>Mtb</italic>. Pharmacological inhibition of PARP decreased intracellular <italic>Mtb</italic> and MDR-<italic>Mtb</italic> levels in human macrophages, identifying PARP as a potential target for host-directed therapy against <italic>Mtb</italic>. PARP inhibition was associated with modified chemokine secretion and upregulation of cell surface activation markers by human macrophages. Targeting LDH, a secondary target of the PARP inhibitor rucaparib, resulted in decreased intracellular <italic>Mtb</italic>, suggesting a metabolic role in rucaparib-induced control of <italic>Mtb</italic>. We conclude that pharmacological inhibition of PARP is a potential novel strategy in developing innovative host-directed therapies against intracellular bacterial infections.</p>