Proapoptotic Bcl-2 inhibitor as potential host directed therapy for pulmonary tuberculosis
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 tubercul...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58190-x |
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| author | 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 |
| author_facet | 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 |
| author_sort | Medha Singh |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-5f3f551ab2944400a513add3e07905d8 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-5f3f551ab2944400a513add3e07905d82025-08-20T03:40:45ZengNature PortfolioNature Communications2041-17232025-03-0116111310.1038/s41467-025-58190-xProapoptotic Bcl-2 inhibitor as potential host directed therapy for pulmonary tuberculosisMedha Singh0Mona O. Sarhan1Nerketa N. L. Damiba2Alok K. Singh3Andres Villabona-Rueda4Oscar J. Nino-Meza5Xueyi Chen6Yuderleys Masias-Leon7Carlos E. Ruiz-Gonzalez8Alvaro A. Ordonez9Franco R. D’Alessio10Eric O. Aboagye11Laurence S. Carroll12Sanjay K. Jain13Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of MedicineCenter for Infection and Inflammation Imaging Research, Johns Hopkins University School of MedicineCenter for Infection and Inflammation Imaging Research, Johns Hopkins University School of MedicineCenter for Infection and Inflammation Imaging Research, Johns Hopkins University School of MedicineDepartment of Medicine, Johns Hopkins University School of MedicineCenter for Infection and Inflammation Imaging Research, Johns Hopkins University School of MedicineCenter for Infection and Inflammation Imaging Research, Johns Hopkins University School of MedicineCenter for Infection and Inflammation Imaging Research, Johns Hopkins University School of MedicineCenter for Infection and Inflammation Imaging Research, Johns Hopkins University School of MedicineCenter for Infection and Inflammation Imaging Research, Johns Hopkins University School of MedicineDepartment of Medicine, Johns Hopkins University School of MedicineComprehensive Cancer Imaging Centre, Department of Surgery & Cancer, Hammersmith Campus, Imperial CollegeRussell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of MedicineCenter for Infection and Inflammation Imaging Research, Johns Hopkins University School of MedicineAbstract 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.https://doi.org/10.1038/s41467-025-58190-x |
| spellingShingle | 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 Proapoptotic Bcl-2 inhibitor as potential host directed therapy for pulmonary tuberculosis Nature Communications |
| title | Proapoptotic Bcl-2 inhibitor as potential host directed therapy for pulmonary tuberculosis |
| title_full | Proapoptotic Bcl-2 inhibitor as potential host directed therapy for pulmonary tuberculosis |
| title_fullStr | Proapoptotic Bcl-2 inhibitor as potential host directed therapy for pulmonary tuberculosis |
| title_full_unstemmed | Proapoptotic Bcl-2 inhibitor as potential host directed therapy for pulmonary tuberculosis |
| title_short | Proapoptotic Bcl-2 inhibitor as potential host directed therapy for pulmonary tuberculosis |
| title_sort | proapoptotic bcl 2 inhibitor as potential host directed therapy for pulmonary tuberculosis |
| url | https://doi.org/10.1038/s41467-025-58190-x |
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