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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Deletion of TolC orthologs in Francisella tularensis identifies roles in multidrug resistance and virulence
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Deletion of TolC orthologs in Francisella tularensis identifies roles in multidrug resistance and virulence

机译：土拉弗朗西斯菌中TolC直系同源物的删除确定了在多药耐药性和毒力中的作用

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摘要

The Gram-negative bacterium Francisella tularensis is the causative agent of tularemia. Interest in this zoonotic pathogen has increased due to its classification as a category A agent of bioterrorism, but little is known about the molecular mechanisms underlying its virulence, and especially what secretion systems and virulence factors are present. In this study, we characterized two genes in the F. tularensis genome, toIC and a gene we term fltC, whose products have high homology with the Escherichia coli ToIC protein. ToIC functions as the outer membrane channel component for both type I secretion and multidrug efflux systems. We constructed deletion mutations of these genes in the F. tularensis live vaccine strain by allelic replacement. Deletion of either toIC or WC caused increased sensitivity to various antibiotics, detergents, and dyes, indicating both genes are involved in the multidrug resistance machinery of F. tularensis. Complementation of the deletion mutations in trans restored drug resistance. Neither toIC nor fltC was required for replication of the live vaccine strain in murine bone marrow-derived macrophages. However, deletion of toIC, but not fltC, caused a significant attenuation of virulence in a mouse model of tularemia that could be complemented by addition of toIC in trans. Thus, toIC is a critical virulence factor of F. tularensis in addition to its role in multidrug resistance, which suggests the presence of a functional type I secretion system.
机译：革兰氏阴性菌tularensis是tularemia的病原体。由于这种人畜共患病原体被归类为A类生物恐怖活动媒介，因此人们对此的兴趣有所增加，但对其毒力的分子机制（尤其是存在哪些分泌系统和毒力因子）了解甚少。在这项研究中，我们表征了F. tularensis基因组中的两个基因toIC和一个我们称为fltC的基因，其产物与大肠杆菌ToIC蛋白具有高度同源性。 ToIC充当I型分泌和多种药物外排系统的外膜通道成分。通过等位基因置换，我们构建了图拉菌活疫苗株中这些基因的缺失突变。 toIC或WC的缺失导致对各种抗生素，去污剂和染料的敏感性增加，表明这两个基因都参与了土拉弗朗西斯菌的多药耐药机制。反式中缺失突变的补充恢复了耐药性。在小鼠骨髓衍生的巨噬细胞中复制活疫苗株不需要toIC或fltC。但是，toic的缺失而不是fltC的缺失导致鼠李糖血症小鼠模型的毒力显着减弱，这可以通过反式添加toIC来补充。因此，toIC除了在多药耐药性中发挥作用外，它还是图莱劳斯菌的关键毒力因子，这表明存在功能性I型分泌系统。

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