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l-阿拉伯糖代谢与毒力调节相结合促进肠道病原体适应性

Metabolism of l-arabinose converges with virulence regulation to promote enteric pathogen fitness

Nature 等信源发布 2024-05-25 20:16

可切换为仅中文


AbstractVirulence and metabolism are often interlinked to control the expression of essential colonisation factors in response to host-associated signals. Here, we identified an uncharacterised transporter of the dietary monosaccharide ʟ-arabinose that is widely encoded by the zoonotic pathogen enterohaemorrhagic Escherichia coli (EHEC), required for full competitive fitness in the mouse gut and highly expressed during human infection.

摘要毒力和代谢通常是相互关联的,以控制响应宿主相关信号的必需定植因子的表达。在这里,我们确定了膳食单糖ʟ-阿拉伯糖的未表征转运蛋白,该转运蛋白由人畜共患病原体肠出血性大肠杆菌(EHEC)广泛编码,是小鼠肠道完全竞争适应性所必需的,并且在人类感染期间高度表达。

Discovery of this transporter suggested that EHEC strains have an enhanced ability to scavenge ʟ-arabinose and therefore prompted us to investigate the impact of this nutrient on pathogenesis. Accordingly, we discovered that ʟ-arabinose enhances expression of the EHEC type 3 secretion system, increasing its ability to colonise host cells, and that the underlying mechanism is dependent on products of its catabolism rather than the sensing of ʟ-arabinose as a signal.

这种转运蛋白的发现表明EHEC菌株具有增强的清除β-阿拉伯糖的能力,因此促使我们研究这种营养素对发病机制的影响。因此,我们发现ʟ-阿拉伯糖增强了EHEC 3型分泌系统的表达,增加了其定殖宿主细胞的能力,并且其潜在机制取决于其分解代谢产物,而不是将ʟ-阿拉伯糖感知为信号。

Furthermore, using the murine pathogen Citrobacter rodentium, we show that ʟ-arabinose metabolism provides a fitness benefit during infection via virulence factor regulation, as opposed to supporting pathogen growth. Finally, we show that this mechanism is not restricted to ʟ-arabinose and extends to other pentose sugars with a similar metabolic fate.

此外,使用鼠病原体柠檬酸杆菌(Citrobacter rodentium),我们表明ʟ-阿拉伯糖代谢通过毒力因子调节在感染期间提供了适应性益处,而不是支持病原体的生长。最后,我们表明,这种机制不仅限于ʟ-阿拉伯糖,还扩展到其他具有类似代谢命运的戊糖。

This work highlights the importance integrating central metabolism with virulence regulation in order to maximise competitive fitness of enteric pathogens within the host-niche..

这项工作强调了将中枢代谢与毒力调节相结合的重要性,以最大限度地提高肠道病原体在宿主生态位内的竞争适应性。。

IntroductionThe mammalian gastrointestinal tract poses a formidable barrier to infection by foreign pathogens. Invaders must sidestep a combination of intrinsic host defences as well as overcome colonisation resistance by the native gut microbiota1. Accordingly, bacterial pathogens have evolved many unique strategies to effectively compete with the microbiota and cause infection within a favourable host-niche2.

引言哺乳动物胃肠道对外来病原体的感染构成了强大的屏障。入侵者必须避开内在宿主防御的组合,并克服天然肠道微生物群的定殖阻力1。因此,细菌病原体已经发展出许多独特的策略来有效地与微生物群竞争并在有利的宿主-niche2内引起感染。

This includes a combination of pathogen-specific virulence mechanisms and metabolic adaptations that increase within-host fitness. Importantly, virulence and fitness factor regulation often coincide and are dynamically controlled in response to the host environment to maximise competitiveness therein3,4,5.Enterohaemorrhagic Escherichia coli (EHEC) is a zoonotic pathogen that is carried asymptomatically by ruminant mammals and transmitted to human hosts typically via contaminated meat and fresh produce.

这包括病原体特异性毒力机制和在宿主适应性内增加的代谢适应的组合。重要的是,毒力和适应因子的调节通常是一致的,并根据宿主环境进行动态控制,以最大程度地提高其竞争力3,4,5。肠出血性大肠杆菌(EHEC)是一种人畜共患病原体,由反刍哺乳动物无症状携带,通常通过受污染的肉类和新鲜农产品传播给人类宿主。

In humans, EHEC causes severe diarrhoeal illness and, in extreme cases, renal failure6,7. EHEC is a member of the attaching and effacing (A/E) family of pathogens, which intimately colonise the colonic epithelium forming characteristic pedestal-like lesions on the surface of host cells8,9. A/E pathogenesis is defined by the activity of a type 3 secretion system (T3SS) encoded on a ~35 kb horizontally acquired island known as the locus of enterocyte effacement (LEE)10,11,12.

在人类中,肠出血性大肠杆菌会导致严重的腹泻病,在极端情况下还会导致肾衰竭6,7。EHEC是附着和消除(a/E)病原体家族的成员,其紧密定植于结肠上皮,在宿主细胞表面形成特征性的基座状病变8,9。A/E发病机制由〜35编码的3型分泌系统(T3SS)的活性定义 kb水平获得的岛被称为肠上皮细胞消失(LEE)的基因座10,11,12。

This T3SS translocates more than 30 effector proteins - encoded on the LEE and several additional horizontally acquired elements, termed O-islands (OIs) - that collectively subvert host-cell function13,14,15,16. The murine pathogen Citrobacter rodentium also encodes the LEE and has been adopted as the relevant surrogate model to study EHEC pathogenesis in vivo due to its dependency on the T3SS, .

该T3SS易位超过30种效应蛋白-编码在LEE上和另外几个水平获得的元件,称为O岛(OIs)-共同破坏宿主细胞功能13,14,15,16。鼠类病原体柠檬酸杆菌(Citrobacter rodentium)也编码LEE,由于其对T3SS的依赖性,已被用作研究体内EHEC发病机理的相关替代模型。

Data availability

数据可用性

The transcriptomic sequencing data is available from the NCBI Gene Expression Omnibus under the accession number GSE262155. The source data for Figs. 2–6, Supplementary Figs. 3–5 and 7–12 are provided as a Source Data file. Publicly available genome sequences were obtained from the NCBI Sequence Read Archive. Source data are provided with this paper..

转录组测序数据可从NCBI Gene Expression Omnibus获得,登录号为GSE262155。图2-6、补充图3-5和7-12的源数据作为源数据文件提供。公开可用的基因组序列是从NCBI序列读取档案中获得的。本文提供了源数据。。

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Download referencesAcknowledgementsWe are very grateful to Dr Nicky O’Boyle, Dr Kate Beckham and Dr Kesha Josts for their critical appraisal of the work. We also would like to thank Professor Janet Quinn for microscope access, the Comparative Biology Centre staff for their support with the animal studies and the Newcastle University Genomics Core Facility for RNA-sequencing.

下载参考文献致谢我们非常感谢Nicky O'Boyle博士,Kate Beckham博士和Kesha Josts博士对这项工作的批判性评估。我们还要感谢Janet Quinn教授的显微镜访问,比较生物学中心工作人员对动物研究的支持以及纽卡斯尔大学基因组学RNA测序核心设施。

This work was supported by a Springboard Award from the Academy of Medical Sciences/Wellcome Trust [SBF005\1029], a Royal Society Research Grant [RGS\R2\202100], a Medical Research Council Career Development Award [MR/X007197/1] and a Faculty Fellowship (Newcastle University) awarded to J.P.R.C. E.C.L was supported by a Wellcome Trust Discovery Award [226644/Z/22/Z].

这项工作得到了医学科学院/惠康基金会的跳板奖[SBF005-1029],皇家学会研究基金[RGS-202100],医学研究委员会职业发展奖[MR/X007197/1]和授予J.P.R.C.的教师奖学金(纽卡斯尔大学)的支持。E.C.L得到了惠康基金会发现奖[226644/Z/22/Z]的支持。

C.C. was supported by a PhD studentship from the Barbour Foundation.Author informationAuthors and AffiliationsNewcastle University Biosciences Institute, Newcastle University, NE2 4HH, Newcastle-upon-Tyne, UKCurtis Cottam, Elisabeth C. Lowe & James P. R. ConnollyInstitute of Environmental Science and Research, Wellington, New ZealandRhys T.

C、 C.得到了巴伯基金会的博士生资助。作者信息作者和附属机构纽卡斯尔大学生物科学研究所,纽卡斯尔大学,NE2 4HH,泰恩河畔纽卡斯尔,UKCurtis Cottam,Elisabeth C.Lowe&James P.R.ConnollyInstitute of Environmental Science and Research,惠灵顿,新西兰Rhys T。

WhiteAustralian Infectious Diseases Research Centre and School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, AustraliaRhys T. White & Scott A. BeatsonNewcastle University Translation and Clinical Research Institute, Newcastle University, NE2 4HH, Newcastle-upon-Tyne, UKLauren C.

澳大利亚昆士兰大学澳大利亚传染病研究中心和化学与分子生物科学学院,澳大利亚昆士兰布里斯班Arhys T.White&Scott A.BeatsonNewcastle University Translation and Clinical Research Institute,纽卡斯尔大学,NE2 4HH,纽卡斯尔泰恩河畔纽卡斯尔,UKLauren C。

Beck & Christopher J. StewartDepartment of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, AustraliaRhys GrinterAuthorsCurtis CottamView author publicationsYou can also search for this author in.

贝克和克里斯托弗·斯图尔特(Beck&ChristopherJ.Stewart)莫纳什大学生物医学发现研究所微生物学系,澳大利亚维多利亚州克莱顿(Clayton),Arhys GrinterauthorsCurtisCottamview作者出版物您也可以在中搜索这位作者。

PubMed Google ScholarRhys T. WhiteView author publicationsYou can also search for this author in

PubMed Google ScholarRhys T.WhiteView作者出版物您也可以在

PubMed Google ScholarLauren C. BeckView author publicationsYou can also search for this author in

PubMed Google ScholarLauren C.BeckView作者出版物您也可以在

PubMed Google ScholarChristopher J. StewartView author publicationsYou can also search for this author in

PubMed Google ScholarChristopher J.StewartView作者出版物您也可以在

PubMed Google ScholarScott A. BeatsonView author publicationsYou can also search for this author in

PubMed Google ScholarScott A.BeatsonView作者出版物您也可以在

PubMed Google ScholarElisabeth C. LoweView author publicationsYou can also search for this author in

PubMed Google ScholarElisabeth C.LoweView作者出版物您也可以在

PubMed Google ScholarRhys GrinterView author publicationsYou can also search for this author in

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PubMed谷歌学者James P.R.ConnollyView作者出版物您也可以在

PubMed Google ScholarContributionsC.C. and J.P.R.C conceptualised and designed the research. C.C., R.T.W. and J.P.R.C. performed the research. C.C., R.T.W., L.C.B., R.G. and J.P.R.C. analysed the data. C.J.S., S.A.B., R.G., E.C.L. and J.P.R.C. contributed reagents/analytical tools.

PubMed谷歌学术贡献中心。C、 J.P.R.C对这项研究进行了概念化和设计。C、 C.,R.T.W.和J.P.R.C.进行了这项研究。C、 C.,R.T.W.,L.C.B.,R.G.和J.P.R.C.分析了数据。C、 J.S.,S.A.B.,R.G.,E.C.L.和J.P.R.C.贡献了试剂/分析工具。

C.C. and J.P.R.C. wrote the paper with input from all other authors.Corresponding authorCorrespondence to.

C、 C.和J.P.R.C.在所有其他作者的意见下撰写了这篇论文。对应作者对应。

James P. R. Connolly.Ethics declarations

詹姆斯·P·R·康诺利。道德宣言

Competing interests

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The authors declare no competing interests.

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Reprints and permissionsAbout this articleCite this articleCottam, C., White, R.T., Beck, L.C. et al. Metabolism of l-arabinose converges with virulence regulation to promote enteric pathogen fitness.

转载和许可本文引用本文Cottam,C.,White,R.T.,Beck,L.C.等人。L-阿拉伯糖的代谢与毒力调节相融合,以促进肠道病原体的适应性。

Nat Commun 15, 4462 (2024). https://doi.org/10.1038/s41467-024-48933-7Download citationReceived: 18 December 2023Accepted: 16 May 2024Published: 25 May 2024DOI: https://doi.org/10.1038/s41467-024-48933-7Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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