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

• Published in: Frontiers in immunology Vol. 12; p. 712021
• Main Authors: van Doorn, Cassandra L R, Steenbergen, Sanne A M, Walburg, Kimberley V, Ottenhoff, Tom H M
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 26.11.2021
• Subjects: host-directed therapy; human macrophages; Humans; Immunology; Macrophages - drug effects; Macrophages - microbiology; Mycobacterium tuberculosis - drug effects; poly (ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; rucaparib; Tuberculosis; poly (ADP-ribose) polymerase; host-directed therapy; rucaparib; human macrophages; tuberculosis
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.712021

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 ( is urgently required. Since poly (ADP-ribose) polymerase (PARP) activation has been associated with DM and with infection in mouse models, we have investigated whether PARP inhibition by pharmacological compounds can interfere with host protection against in human macrophage subsets, the predominant target cell of . Pharmacological inhibition of PARP decreased intracellular and MDR- levels in human macrophages, identifying PARP as a potential target for host-directed therapy against . 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 , suggesting a metabolic role in rucaparib-induced control of . We conclude that pharmacological inhibition of PARP is a potential novel strategy in developing innovative host-directed therapies against intracellular bacterial infections.