Mycobacterium tuberculosis exploits the PPM1A signaling pathway to block host macrophage apoptosis.
The ability to suppress host macrophage apoptosis is essential for M. tuberculosis (Mtb) to replicate intracellularly while protecting it from antibiotic treatment. We recently described that Mtb infection upregulated expression of the host phosphatase PPM1A, which impairs the antibacterial response of macrophages. Here we establish PPM1A as a checkpoint target used by Mtb to suppress macrophage apoptosis. Overproduction of PPM1A suppressed apoptosis of Mtb-infected macrophages by a mechanism that involves inactivation of the c-Jun N-terminal kinase (JNK). Targeted depletion of PPM1A by shRNA or inhibition of PPM1A activity by sanguinarine restored JNK activation, resulting in increased apoptosis of Mtb-infected macrophages. We also demonstrate that activation of JNK by subtoxic concentrations of anisomycin induced selective apoptotic killing of Mtb-infected human macrophages, which was completely blocked in the presence of a specific JNK inhibitor. Finally, selective killing of Mtb-infected macrophages and subsequent bacterial release enabled rifampicin to effectively kill Mtb at concentrations that were insufficient to act against intracellular Mtb, providing proof of principle for the efficacy of a "release and kill" strategy. Taken together, these findings suggest that drug-induced selective apoptosis of Mtb-infected macrophages is achievable.
Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Kaitlyn
K
Schaaf
Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Samuel R
SR
Smith
Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Alexandra
A
Duverger
Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Frederic
F
Wagner
Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Frank
F
Wolschendorf
Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Andrew O
AO
Westfall
Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Olaf
O
Kutsch
Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Jim
J
Sun
D000995:Antitubercular Agents / Q000494:pharmacology; D017209:Apoptosis; D002470:Cell Survival; D002478:Cells, Cultured; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D008264:Macrophages / Q000382:microbiology* / Q000502:physiology*; D009169:Mycobacterium tuberculosis / Q000472:pathogenicity*; D000071636:Protein Phosphatase 2C / Q000378:metabolism*; D012293:Rifampin / Q000494:pharmacology; D015398:Signal Transduction
D000995:Antitubercular Agents; C000607456:PPM1A protein, human; D000071636:Protein Phosphatase 2C; D012293:Rifampin