Vaubourgeix Julien, Lin Gang, Dhar Neeraj, Chenouard Nicolas, Jiang Xiuju, Botella Helene, Lupoli Tania, Mariani Olivia, Yang Guangli, Ouerfelli Ouathek, Unser Michael, Schnappinger Dirk, McKinney John, Nathan Carl
Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065, USA.
School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), SV 3834, Station 19, CH-1015 Lausanne, Switzerland.
Cell Host Microbe. 2015 Feb 11;17(2):178-90. doi: 10.1016/j.chom.2014.12.008. Epub 2015 Jan 22.
Mycobacterium tuberculosis (Mtb) defends itself against host immunity and chemotherapy at several levels, including the repair or degradation of irreversibly oxidized proteins (IOPs). To investigate how Mtb deals with IOPs that can neither be repaired nor degraded, we used new chemical and biochemical probes and improved image analysis algorithms for time-lapse microscopy to reveal a defense against stationary phase stress, oxidants, and antibiotics--the sequestration of IOPs into aggregates in association with the chaperone ClpB, followed by the asymmetric distribution of aggregates within bacteria and between their progeny. Progeny born with minimal IOPs grew faster and better survived a subsequent antibiotic stress than their IOP-burdened sibs. ClpB-deficient Mtb had a marked recovery defect from stationary phase or antibiotic exposure and survived poorly in mice. Treatment of tuberculosis might be assisted by drugs that cripple the pathway by which Mtb buffers, sequesters, and asymmetrically distributes IOPs.
结核分枝杆菌（Mtb）在多个层面抵御宿主免疫和化疗，包括对不可逆氧化蛋白（IOPs）的修复或降解。为了研究Mtb如何处理既无法修复也无法降解的IOPs，我们使用了新的化学和生化探针以及改进的延时显微镜图像分析算法，以揭示其对稳定期应激、氧化剂和抗生素的防御机制——将IOPs与伴侣蛋白ClpB结合形成聚集体，随后聚集体在细菌内部及其子代之间不对称分布。与携带大量IOPs的子代相比，携带少量IOPs出生的子代生长更快，在随后的抗生素应激中存活得更好。缺乏ClpB的Mtb在稳定期或抗生素暴露后的恢复存在明显缺陷，在小鼠体内存活能力较差。削弱Mtb缓冲、隔离和不对称分布IOPs途径的药物可能有助于结核病的治疗。
