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Proapoptotic Bcl-2 inhibitor as potential host directed therapy for pulmonary tuberculosis

Author

Listed:
  • Medha Singh

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Mona O. Sarhan

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Nerketa N. L. Damiba

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Alok K. Singh

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Amity University)

  • Andres Villabona-Rueda

    (Johns Hopkins University School of Medicine)

  • Oscar J. Nino-Meza

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Xueyi Chen

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Yuderleys Masias-Leon

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Carlos E. Ruiz-Gonzalez

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Alvaro A. Ordonez

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Franco R. D’Alessio

    (Johns Hopkins University School of Medicine)

  • Eric O. Aboagye

    (Imperial College)

  • Laurence S. Carroll

    (Johns Hopkins University School of Medicine)

  • Sanjay K. Jain

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

Abstract

Mycobacterium tuberculosis establishes within host cells by inducing anti-apoptotic Bcl-2 family proteins, triggering necrosis, inflammation, and fibrosis. Here, we demonstrate that navitoclax, an orally bioavailable, small-molecule Bcl-2 inhibitor, significantly improves pulmonary tuberculosis (TB) treatments as a host-directed therapy. Addition of navitoclax to standard TB treatments at human equipotent dosing in mouse models of TB, inhibits Bcl-2 expression, leading to improved bacterial clearance, reduced tissue necrosis, fibrosis and decreased extrapulmonary bacterial dissemination. Using immunohistochemistry and flow cytometry, we show that navitoclax induces apoptosis in several immune cells, including CD68+ and CD11b+ cells. Finally, positron emission tomography (PET) in live animals using clinically translatable biomarkers for apoptosis (18F-ICMT-11) and fibrosis (18F-FAPI-74), demonstrates that navitoclax significantly increases apoptosis and reduces fibrosis in pulmonary tissues, which are confirmed in postmortem analysis. Our studies suggest that proapoptotic drugs such as navitoclax can potentially improve pulmonary TB treatments, reduce lung damage / fibrosis and may be protective against post-TB lung disease.

Suggested Citation

  • Medha Singh & Mona O. Sarhan & Nerketa N. L. Damiba & Alok K. Singh & Andres Villabona-Rueda & Oscar J. Nino-Meza & Xueyi Chen & Yuderleys Masias-Leon & Carlos E. Ruiz-Gonzalez & Alvaro A. Ordonez & F, 2025. "Proapoptotic Bcl-2 inhibitor as potential host directed therapy for pulmonary tuberculosis," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58190-x
    DOI: 10.1038/s41467-025-58190-x
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    References listed on IDEAS

    as
    1. Xueyi Chen & Bhavatharini Arun & Oscar J. Nino-Meza & Mona O. Sarhan & Medha Singh & Byeonghoon Jeon & Kishor Mane & Maunank Shah & Elizabeth W. Tucker & Laurence S. Carroll & Joel S. Freundlich & Cha, 2024. "Dynamic PET reveals compartmentalized brain and lung tissue antibiotic exposures of tuberculosis drugs," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    2. Filipa Mota & Camilo A. Ruiz-Bedoya & Elizabeth W. Tucker & Daniel P. Holt & Patricia Jesus & Martin A. Lodge & Clara Erice & Xueyi Chen & Melissa Bahr & Kelly Flavahan & John Kim & Mary Katherine Bro, 2022. "Dynamic 18F-Pretomanid PET imaging in animal models of TB meningitis and human studies," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    3. Hui Pan & Bo-Shiun Yan & Mauricio Rojas & Yuriy V. Shebzukhov & Hongwei Zhou & Lester Kobzik & Darren E. Higgins & Mark J. Daly & Barry R. Bloom & Igor Kramnik, 2005. "Ipr1 gene mediates innate immunity to tuberculosis," Nature, Nature, vol. 434(7034), pages 767-772, April.
    4. Berit Carow & Thomas Hauling & Xiaoyan Qian & Igor Kramnik & Mats Nilsson & Martin E. Rottenberg, 2019. "Spatial and temporal localization of immune transcripts defines hallmarks and diversity in the tuberculosis granuloma," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    Full references (including those not matched with items on IDEAS)

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