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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Positive selection identifies an in vivo role for FimH during urinary tract infection in addition to mannose binding
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Positive selection identifies an in vivo role for FimH during urinary tract infection in addition to mannose binding

机译：阳性选择确定了FimH在尿路感染期间除甘露糖结合外的体内作用

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摘要

FimH, the type 1 pilus adhesin of uropathogenic Escherichia coli (UPEC), contains a receptor-binding domain with an acidic binding pocket specific for mannose. The fim operpn, and thus type 1 pilus production, is under transcriptional control via phase variation of an invertible promoter element. FimH is critical during urinary tract infection for mediating colonization and invasion of the bladder epithelium and establishment of intracellular bacterial communities (IBCs). In silico analysis of FimH gene sequences from 279 E. coli strains identified specific amino acids evolving under positive selection outside of its mannose-binding pocket. Mutating two of these residues (A27V/V163A) had no effect on phase variation, pilus assembly, or mannose binding in vitro. However, compared to wild-type, this double mutant strain exhibited a 10,000-fold reduction in mouse bladder colonization 24 h after inoculation and was unable to form IBCs even though it bound normally to mannosylated receptors in the urothelium. In contrast, the single A62S mutation altered phase variation, reducing the proportion of piliated cells, reduced mannose binding 8-fold, and decreased bladder colonization 30-fold in vivo compared to wild-type. A phase-locked ON A62S mutant restored virulence to wild-type levels even though in vitro mannose binding remained impaired. Thus, positive selection analysis of FimH has separated mannose binding from in vivo fitness, suggesting that IBC formation is critical for successful infection of the mammalian bladder, providing support for more general use of in silico positive selection analysis to define the molecular underpinnings of bacterial pathogenesis.
机译：FimH，尿毒症性大肠杆菌（UPEC）的1型菌毛粘附素，包含一个受体结合域，该域具有一个对甘露糖具有特异性的酸性结合袋。通过可逆启动子元件的相变，fim操作蛋白以及1型菌毛的产生处于转录控制之下。在尿路感染中，FimH对于介导膀胱上皮的定植和侵袭以及细胞内细菌群落（IBC）的建立至关重要。在计算机分析来自279株大肠杆菌的FimH基因序列时，确定了在其甘露糖结合口袋之外的正选择作用下进化出的特定氨基酸。在体外突变其中两个残基（A27V / V163A）对相变，菌毛组装或甘露糖结合均无影响。但是，与野生型相比，这种双重突变菌株在接种后24小时小鼠膀胱定植减少了10,000倍，即使它通常与尿路上皮中的甘露糖基化受体结合，也无法形成IBC。相比之下，与野生型相比，单个A62S突变改变了相变，减少了有毛细胞的比例，减少了8倍的甘露糖结合，减少了30倍的膀胱定植。一个锁相的ON A62S突变体将毒力恢复到了野生型水平，即使体外甘露糖结合仍然受到损害。因此，FimH的阳性选择分析已将甘露糖结合与体内适应性分离开来，表明IBC的形成对于成功感染哺乳动物膀胱至关重要，这为更广泛地利用计算机上的阳性选择分析确定细菌发病机理的分子基础提供了支持。 。

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  • 作者

    Swaine L. Chen; Chia S. Hung; Jerome S. Pinkner; Jennifer N. Walker; Corinne K. Cusumano; Zhaoli Li; Julie Bouckaert; Jeffrey I. Gordon; Scott J. Hultgren;

  • 作者单位

    Department of Molecular Microbiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110;

    Department of Molecular Microbiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110;

    Department of Molecular Microbiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110;

    Department of Molecular Microbiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110;

    Department of Molecular Microbiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110;

    Viral Genetics, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium;

    Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium Department of Molecular and Cellular Interactions, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium;

    Center for Genome Sciences, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110;

    Department of Molecular Microbiology, Center for Women's Infectious Disease Research, 660 South Euclid Avenue, St. Louis, MO 63110;

  • 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

    type 1 pili; uropathogenic escherichia coli;

    机译：1型菌毛;尿毒原性大肠杆菌;

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