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Mycobacterium tuberculosis exploits the PPM1A signaling pathway to block host macrophage apoptosis.
Schaaf, Kaitlyn; Smith, Samuel R; Duverger, Alexandra; Wagner, Frederic; Wolschendorf, Frank; Westfall, Andrew O; Kutsch, Olaf; Sun, Jim.
Afiliação
  • Schaaf K; Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
  • Smith SR; Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
  • Duverger A; Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
  • Wagner F; Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
  • Wolschendorf F; Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
  • Westfall AO; Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
  • Kutsch O; Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
  • Sun J; Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Sci Rep ; 7: 42101, 2017 02 08.
Article em En | MEDLINE | ID: mdl-28176854
ABSTRACT
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Interações Hospedeiro-Patógeno / Evasão da Resposta Imune / Proteína Fosfatase 2C / Macrófagos / Mycobacterium tuberculosis Limite: Humans Idioma: En Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Interações Hospedeiro-Patógeno / Evasão da Resposta Imune / Proteína Fosfatase 2C / Macrófagos / Mycobacterium tuberculosis Limite: Humans Idioma: En Ano de publicação: 2017 Tipo de documento: Article