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 respon...

Full description

Saved in:
Bibliographic Details
Published in:Scientific reports 2017-02, Vol.7 (1), p.42101, Article 42101
Main Authors: Schaaf, Kaitlyn, Smith, Samuel R., Duverger, Alexandra, Wagner, Frederic, Wolschendorf, Frank, Westfall, Andrew O., Kutsch, Olaf, Sun, Jim
Format: Article
Language:English
Subjects:
13/106
13/31
13/89
13/95
14/63
38/1
38/39
631/326/41/2533
631/326/421
631/326/88
692/699/255/1856
Anisomycin
Antitubercular Agents - pharmacology
Apoptosis
c-Jun protein
Cell activation
Cell Survival
Cells, Cultured
Host-Pathogen Interactions
Humanities and Social Sciences
Humans
Immune Evasion
Inactivation
JNK protein
Macrophages
Macrophages - microbiology
Macrophages - physiology
multidisciplinary
Mycobacterium tuberculosis - pathogenicity
Protein Phosphatase 2C - metabolism
Rifampin
Rifampin - pharmacology
Sanguinarine
Science
Signal Transduction
Transcription factors
Tuberculosis
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:2045-2322
2045-2322
DOI:10.1038/srep42101