Scholarlink

<p><i>Mycobacterium tuberculosis</i> 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<sup>+</sup> and CD11b<sup>+</sup> cells. Finally, positron emission tomography (PET) in <i>live</i> animals using clinically translatable biomarkers for apoptosis (<sup>18</sup>F-ICMT-11) and fibrosis (<sup>18</sup>F-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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年3月27日

查看全文
  • 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,
  • Franco R. D’Alessio,
  • Eric O. Aboagye,
  • Laurence S. Carroll,
  • Sanjay K. Jain

摘要

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.