Copper resistance is essential for virulence of Mycobacterium tuberculosis
Copper resistance is essential for virulence of Mycobacterium tuberculosis
复制标题
DOI：
10.1073/pnas.1009261108
复制
发表时间：
2011-01-25
影响因子：
11.1
通讯作者：
Niederweis, Michael
中科院分区：
文献类型：
--
作者：
Wolschendorf, Frank;Ackart, David;Niederweis, Michael
铜（Cu）是许多生物过程所必需的，但当过量存在时是有毒的。在这项研究中，我们提供的证据表明，铜在控制结核病中起着至关重要的作用。缺乏外膜通道蛋白Rv 1698的结核分枝杆菌（Mtb）突变体积累了100倍以上的铜，比WT Mtb更容易受到铜毒性的影响。在M. Smeglobulin突变体缺少同源物Ms 3747，表明这些分枝杆菌铜转运蛋白B（Mct B）对于铜抗性和维持低细胞内铜水平是必需的。豚鼠对结核分枝杆菌感染的反应是增加肺部病变中的铜浓度。在感染结核分枝杆菌的豚鼠中，MctB的缺失导致肺和淋巴结中的细菌负荷分别减少1,000倍和100倍。在小鼠中，Mtb mctB突变体的持久性缺陷通过向饮食中添加Cu而加剧。这些实验提供的证据表明，铜是由哺乳动物宿主控制结核分枝杆菌感染和铜抗性机制是至关重要的结核分枝杆菌毒力。重要的是，Mtb比其他细菌对Cu更敏感，并且在体外被低于巨噬细胞吞噬体中发现的Cu浓度杀死。因此，这项研究揭示了结核病的致命弱点，可能是结核病化疗的一个有前途的目标。
Copper (Cu) is essential for many biological processes, but is toxic when present in excessive amounts. In this study, we provide evidence that Cu plays a crucial role in controlling tuberculosis. A Mycobacterium tuberculosis (Mtb) mutant lacking the outer membrane channel protein Rv1698 accumulated 100-fold more Cu and was more susceptible to Cu toxicity than WT Mtb. Similar phenotypes were observed for a M. smegmatis mutant lacking the homolog Ms3747, demonstrating that these mycobacterial copper transport proteins B (MctB) are essential for Cu resistance and maintenance of low intracellular Cu levels. Guinea pigs responded to infection with Mtb by increasing the Cu concentration in lung lesions. Loss of MctB resulted in a 1,000- and 100-fold reduced bacterial burden in lungs and lymph nodes, respectively, in guinea pigs infected with Mtb. In mice, the persistence defect of the Mtb mctB mutant was exacerbated by the addition of Cu to the diet. These experiments provide evidence that Cu is used by the mammalian host to control Mtb infection and that Cu resistance mechanisms are crucial for Mtb virulence. Importantly, Mtb is much more susceptible to Cu than other bacteria and is killed in vitro by Cu concentrations lower than those found in phagosomes of macrophages. Hence, this study reveals an Achilles heel of Mtb that might be a promising target for tuberculosis chemotherapy.