Singh Medha, Sarhan Mona O, Damiba Nerketa N L, Singh Alok K, Villabona-Rueda Andres, Nino-Meza Oscar J, Chen Xueyi, Masias-Leon Yuderleys, Ruiz-Gonzalez Carlos E, Ordonez Alvaro A, D'Alessio Franco R, Aboagye Eric O, Carroll Laurence S, Jain Sanjay K
Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Nat Commun. 2025 Mar 27;16(1):3003. doi: 10.1038/s41467-025-58190-x.
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 (F-ICMT-11) and fibrosis (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.
结核分枝杆菌通过诱导抗凋亡的Bcl-2家族蛋白在宿主细胞内定植，引发坏死、炎症和纤维化。在此，我们证明了维托克洛司（navitoclax），一种口服生物可利用的小分子Bcl-2抑制剂，作为一种宿主导向疗法可显著改善肺结核（TB）的治疗效果。在肺结核小鼠模型中，以人体等效剂量将维托克洛司添加到标准抗结核治疗中，可抑制Bcl-2表达，从而提高细菌清除率，减少组织坏死、纤维化，并减少肺外细菌播散。通过免疫组织化学和流式细胞术，我们表明维托克洛司可诱导包括CD68和CD11b细胞在内的多种免疫细胞凋亡。最后，使用针对凋亡（F-ICMT-11）和纤维化（F-FAPI-74）的临床可转化生物标志物对活体动物进行正电子发射断层扫描（PET），结果表明维托克洛司可显著增加肺部组织的凋亡并减少纤维化，这在尸检分析中得到了证实。我们的研究表明，像维托克洛司这样的促凋亡药物可能会改善肺结核的治疗效果，减少肺损伤/纤维化，并可能预防肺结核后的肺部疾病。
