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

Cassandra L R van Doorn1, Sanne A M Steenbergen1, Kimberley V Walburg1

  • 1Department of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands.

Frontiers in Immunology
|December 13, 2021
PubMed

Insights

Poly (ADP-ribose) polymerase (PARP) inhibition shows promise for treating tuberculosis (TB) in patients with diabetes mellitus (DM). Targeting PARP in human macrophages reduced Mycobacterium tuberculosis (Mtb) levels, suggesting a new host-directed therapy approach.

Area of Science:

  • Immunology
  • Infectious Diseases
  • Metabolism

Background:

  • Diabetes mellitus (DM) exacerbates tuberculosis (TB) susceptibility and progression, complicating global TB control.
  • Poly (ADP-ribose) polymerase (PARP) activation is linked to both DM and Mycobacterium tuberculosis (Mtb) infection.
  • Understanding the molecular interplay between DM and Mtb immunity is crucial for co-epidemic control.

Purpose of the Study:

  • To investigate the role of PARP inhibition in host defense against Mtb in human macrophages.
  • To explore PARP as a potential target for host-directed therapy against Mtb infections.

Main Methods:

  • Pharmacological inhibition of PARP in human macrophage subsets.
  • Assessment of intracellular Mtb and multidrug-resistant Mtb (MDR-Mtb) levels.
  • Analysis of chemokine secretion and cell surface activation markers.
  • Investigation of lactate dehydrogenase (LDH) targeting.

Main Results:

  • PARP inhibition significantly decreased intracellular Mtb and MDR-Mtb levels in human macrophages.
  • PARP inhibition modulated chemokine secretion and upregulated macrophage activation markers.
  • Targeting LDH, a secondary target of rucaparib, also reduced intracellular Mtb, indicating a metabolic component.

Conclusions:

  • Pharmacological PARP inhibition represents a potential host-directed therapeutic strategy against Mtb.
  • This approach may offer novel treatments for intracellular bacterial infections, particularly in the context of comorbid DM.
Keywords:
host-directed therapyhuman macrophagespoly (ADP-ribose) polymeraserucaparibtuberculosis

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