Fatima Samreen, Kamble Shashank Shivaji, Dwivedi Ved Prakash, Bhattacharya Debapriya, Kumar Santosh, Ranganathan Anand, Van Kaer Luc, Mohanty Sujata, Das Gobardhan
Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, India.
International Centre for Genetic Engineering and Biotechnology, New Delhi, India.
J Clin Invest. 2020 Feb 3;130(2):655-661. doi: 10.1172/JCI128043.
Tuberculosis (TB) remains a major infectious disease worldwide. TB treatment displays a biphasic bacterial clearance, in which the majority of bacteria clear within the first month of treatment, but residual bacteria remain nonresponsive to treatment and eventually may become resistant. Here, we have shown that Mycobacterium tuberculosis was taken up by mesenchymal stem cells (MSCs), where it established dormancy and became highly nonresponsive to isoniazid, a major constituent of directly observed treatment short course (DOTS). Dormant M. tuberculosis induced quiescence in MSCs and promoted their long-term survival. Unlike macrophages, where M. tuberculosis resides in early-phagosomal compartments, in MSCs the majority of bacilli were found in the cytosol, where they promoted rapid lipid synthesis, hiding within lipid droplets. Inhibition of lipid synthesis prevented dormancy and sensitized the organisms to isoniazid. Thus, we have established that M. tuberculosis gains dormancy in MSCs, which serve as a long-term natural reservoir of dormant M. tuberculosis. Interestingly, in the murine model of TB, induction of autophagy eliminated M. tuberculosis from MSCs, and consequently, the addition of rapamycin to an isoniazid treatment regimen successfully attained sterile clearance and prevented disease reactivation.
结核病（TB）仍是全球主要的传染病。结核病治疗呈现出双相细菌清除过程，其中大多数细菌在治疗的第一个月内清除，但残留细菌对治疗无反应，最终可能产生耐药性。在此，我们发现结核分枝杆菌被间充质干细胞（MSC）摄取，在其中进入休眠状态，并对直接观察短程治疗（DOTS）的主要成分异烟肼高度无反应。休眠的结核分枝杆菌诱导MSC静止并促进其长期存活。与结核分枝杆菌存在于早期吞噬体区室的巨噬细胞不同，在MSC中，大多数杆菌存在于细胞质中，在那里它们促进快速脂质合成，并隐藏在脂滴内。抑制脂质合成可防止休眠并使细菌对异烟肼敏感。因此，我们确定结核分枝杆菌在MSC中进入休眠状态，MSC作为休眠结核分枝杆菌的长期天然储存库。有趣的是，在结核病小鼠模型中，自噬的诱导消除了MSC中的结核分枝杆菌，因此，在异烟肼治疗方案中添加雷帕霉素成功实现了无菌清除并预防了疾病复发。
