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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Copper resistance is essential for virulence of Mycobacterium tuberculosis
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Copper resistance is essential for virulence of Mycobacterium tuberculosis

机译：铜抗性对于结核分枝杆菌的毒力至关重要

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摘要

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 pheno-types were observed for a M. smegmatis mutant lacking the homo-log 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 macro-phages. Hence, this study reveals an Achilles heel of Mtb that might be a promising target for tuberculosis chemotherapy.
机译：铜（Cu）对于许多生物过程都是必不可少的，但是如果存在过多，则有毒。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。缺少外膜通道蛋白Rv1698的结核分枝杆菌（Mtb）突变体比WT Mtb多积累了100倍的Cu，并且对Cu的毒性更敏感。对于缺少同源Ms3747的耻垢分枝杆菌突变体，观察到了相似的表型，表明这些分枝杆菌铜转运蛋白B（MctB）对于铜抗性和维持低细胞内铜水平至关重要。豚鼠通过增加肺部病变中的Cu浓度来应对Mtb感染。 MctB的损失分别导致感染Mtb的豚鼠的肺和淋巴结细菌负担减少1000倍和100倍。在小鼠中，饮食中添加铜会加剧Mtb mctB突变体的持久性缺陷。这些实验提供了证据，证明哺乳动物宿主将Cu用于控制Mtb感染，并且Cu抗性机制对于Mtb毒力至关重要。重要的是，与其他细菌相比，Mtb对Cu的敏感性更高，并且在体外会被Cu浓度低于巨噬细胞吞噬体中的Cu浓度杀死。因此，这项研究揭示了Mtb的致命弱点可能是结核化疗的有希望的靶标。

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  • 作者

    Frank Wolschendorf; David Ackart; Tej B. Shrestha; Laurel Hascall-Dove; Scott Nolan; Gyanu Lamichhane; Ying Wang; Stefan H. Bossmann; Randall J. Basaraba; Michael Niederweis;

  • 作者单位

    Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294;

    Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523-1619;

    Department of Chemistry, Kansas State University, Manhattan, KS 66506-0401;

    Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523-1619;

    Tuberculosis Animal Research and Gene Evaluation Taskforce, The Johns Hopkins University School of Medicine, Baltimore, MD 21231;

    Tuberculosis Animal Research and Gene Evaluation Taskforce, The Johns Hopkins University School of Medicine, Baltimore, MD 21231;

    Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294;

    Department of Chemistry, Kansas State University, Manhattan, KS 66506-0401;

    Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523-1619;

    Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    immune system; metal; accumulation;

    机译：免疫系统;金属;积累;

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