LD-transpeptidase-mediated cell envelope remodeling enables developmental transitions and survival in Coxiella burnetii and Legionella pneumophila.

IF 2.7 3区 生物学 Q3 MICROBIOLOGY
Journal of Bacteriology Pub Date : 2025-02-20 Epub Date: 2025-01-23 DOI:10.1128/jb.00247-24
Dipak Kathayat, Yujia Huang, Joee Denis, Benjamin Rudoy, Hana Schwarz, Jacob Szlechter
{"title":"LD-transpeptidase-mediated cell envelope remodeling enables developmental transitions and survival in <i>Coxiella burnetii</i> and <i>Legionella pneumophila</i>.","authors":"Dipak Kathayat, Yujia Huang, Joee Denis, Benjamin Rudoy, Hana Schwarz, Jacob Szlechter","doi":"10.1128/jb.00247-24","DOIUrl":null,"url":null,"abstract":"<p><p><i>Coxiella burnetii</i> and <i>Legionella pneumophila</i> are two phylogenetically related bacterial pathogens that exhibit extreme intrinsic resistance when they enter into a dormancy-like state. This enables both pathogens to survive extended periods in growth-limited environments. Survival is dependent upon their ability to undergo developmental transitions into two phenotypically distinct variants, one specialized for intracellular replication and another for prolonged survival in the environment and host. We currently lack an understanding of the mechanisms that mediate these developmental transitions. Here, we performed peptidoglycan (PG) glycoproteome analysis and showed significant enrichment of PG structures catalyzed by LD-transpeptidases (LDTs) in the survival variants of <i>C. burnetii</i> and <i>L. pneumophila</i>. This is supported by the upregulation of LDTs, resulting in susceptibility to carbapenem antibiotics. Furthermore, deletion of the most upregulated LDT, <i>lpg</i>1386, in <i>L. pneumophila</i> significantly changes PG architecture, survival, and susceptibility to antibiotics. Significantly regulated by RpoS, a stationary-phase sigma factor, LDT-dependent PG remodeling is differentially activated by the host intracellular growth environment compared to axenic culture. In addition, β-barrel tethering, a newly discovered mechanism of LDT-mediated cell envelope stabilization, seems not to be specific to the survival variants. Interestingly, an outer membrane (OM) long-chain fatty acid transporter (Lpg1810) is tethered to PG in <i>L. pneumophila</i>. Collectively, these findings show that LDT-mediated PG remodeling is a major determinant of developmental transitions and survival in <i>C. burnetii</i> and <i>L. pneumophila</i>. Understanding this mechanism might inform new therapeutic approaches for treating chronic infections caused by these pathogens, as well as suggest new methods to decontaminate environmental reservoirs during outbreaks.IMPORTANCE<i>Coxiella burnetii</i> and <i>L. pneumophila</i> cause Q Fever and Legionnaire's disease in humans, respectively. There is a lack of effective treatments for fatal chronic infections caused by these pathogens, particularly chronic Q Fever. These bacteria survive long term in nutrient-limited environments by differentiating into phenotypically distinct survival variants. Our study revealed that LDTs, a group of PG remodeling enzymes, play a prominent role in the phenotypic differentiations of these bacteria. We show that LDT-targeting carbapenems are effective against the survival variants, thus demanding the exploration of carbapenems for treating chronic infections caused by these pathogens. We report the tethering of a unique OM fatty acid transporter to PG in <i>L. pneumophila</i> that could indicate a novel function of tethering, that is, the uptake of nutrient substrates. Homologs of this transporter are widely present in the Methylobacteriaceae family of bacteria known to survive in water systems like <i>Legionella</i>, thus suggesting a potentially conserved mechanism of bacterial survival in nutrient-limited environments.</p>","PeriodicalId":15107,"journal":{"name":"Journal of Bacteriology","volume":" ","pages":"e0024724"},"PeriodicalIF":2.7000,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11841132/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Bacteriology","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1128/jb.00247-24","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/23 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Coxiella burnetii and Legionella pneumophila are two phylogenetically related bacterial pathogens that exhibit extreme intrinsic resistance when they enter into a dormancy-like state. This enables both pathogens to survive extended periods in growth-limited environments. Survival is dependent upon their ability to undergo developmental transitions into two phenotypically distinct variants, one specialized for intracellular replication and another for prolonged survival in the environment and host. We currently lack an understanding of the mechanisms that mediate these developmental transitions. Here, we performed peptidoglycan (PG) glycoproteome analysis and showed significant enrichment of PG structures catalyzed by LD-transpeptidases (LDTs) in the survival variants of C. burnetii and L. pneumophila. This is supported by the upregulation of LDTs, resulting in susceptibility to carbapenem antibiotics. Furthermore, deletion of the most upregulated LDT, lpg1386, in L. pneumophila significantly changes PG architecture, survival, and susceptibility to antibiotics. Significantly regulated by RpoS, a stationary-phase sigma factor, LDT-dependent PG remodeling is differentially activated by the host intracellular growth environment compared to axenic culture. In addition, β-barrel tethering, a newly discovered mechanism of LDT-mediated cell envelope stabilization, seems not to be specific to the survival variants. Interestingly, an outer membrane (OM) long-chain fatty acid transporter (Lpg1810) is tethered to PG in L. pneumophila. Collectively, these findings show that LDT-mediated PG remodeling is a major determinant of developmental transitions and survival in C. burnetii and L. pneumophila. Understanding this mechanism might inform new therapeutic approaches for treating chronic infections caused by these pathogens, as well as suggest new methods to decontaminate environmental reservoirs during outbreaks.IMPORTANCECoxiella burnetii and L. pneumophila cause Q Fever and Legionnaire's disease in humans, respectively. There is a lack of effective treatments for fatal chronic infections caused by these pathogens, particularly chronic Q Fever. These bacteria survive long term in nutrient-limited environments by differentiating into phenotypically distinct survival variants. Our study revealed that LDTs, a group of PG remodeling enzymes, play a prominent role in the phenotypic differentiations of these bacteria. We show that LDT-targeting carbapenems are effective against the survival variants, thus demanding the exploration of carbapenems for treating chronic infections caused by these pathogens. We report the tethering of a unique OM fatty acid transporter to PG in L. pneumophila that could indicate a novel function of tethering, that is, the uptake of nutrient substrates. Homologs of this transporter are widely present in the Methylobacteriaceae family of bacteria known to survive in water systems like Legionella, thus suggesting a potentially conserved mechanism of bacterial survival in nutrient-limited environments.

ld -转肽酶介导的细胞包膜重塑促进伯纳氏杆菌和嗜肺军团菌的发育转变和存活。
伯纳蒂克希菌和嗜肺军团菌是两种系统发育相关的细菌病原体,当它们进入休眠状态时表现出极端的内在抗性。这使两种病原体能够在生长受限的环境中存活较长时间。生存依赖于它们经历发育转变为两种不同表型变体的能力,一种专门用于细胞内复制,另一种用于在环境和宿主中延长生存时间。我们目前缺乏对这些发育转变的机制的理解。在这里,我们进行了肽聚糖(PG)糖蛋白组分析,发现在伯氏梭菌和嗜肺乳杆菌的存活变体中,由ld转肽酶(LDTs)催化的PG结构显著富集。LDTs的上调导致对碳青霉烯类抗生素的易感性支持了这一点。此外,在嗜肺乳杆菌中,缺失最上调的LDT lpg1386显著改变了PG的结构、存活和对抗生素的敏感性。受RpoS(一种静止期sigma因子)的显著调控,ldt依赖性PG重塑在宿主细胞内生长环境下被激活的程度与无菌培养不同。此外,新发现的ldt介导的细胞包膜稳定机制β-桶系固(β-barrel tethering)似乎并非仅针对存活变异体。有趣的是,嗜肺乳杆菌的外膜(OM)长链脂肪酸转运蛋白(Lpg1810)被拴在PG上。总的来说,这些发现表明ldt介导的PG重塑是伯氏梭菌和嗜肺乳杆菌发育转变和存活的主要决定因素。了解这一机制可能为治疗由这些病原体引起的慢性感染提供新的治疗方法,并提出在暴发期间净化环境水库的新方法。重要意义伯氏杆菌和嗜肺乳杆菌分别引起人类Q热和军团病。对于由这些病原体引起的致命慢性感染,特别是慢性Q热,缺乏有效的治疗方法。这些细菌通过分化成表型上不同的生存变体,在营养有限的环境中长期存活。我们的研究表明LDTs是一组PG重塑酶,在这些细菌的表型分化中起着突出的作用。我们发现靶向ldt的碳青霉烯类药物对存活变异有效,因此需要探索碳青霉烯类药物治疗由这些病原体引起的慢性感染。我们报道了嗜肺乳杆菌中一种独特的OM脂肪酸转运蛋白与PG的系结,这可能表明系结的一种新功能,即对营养底物的吸收。这种转运体的同源物广泛存在于甲基杆菌科细菌中,这些细菌已知在军团菌等水系统中存活,从而表明细菌在营养有限的环境中存活的潜在保守机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Journal of Bacteriology
Journal of Bacteriology 生物-微生物学
CiteScore
6.10
自引率
9.40%
发文量
324
审稿时长
1.3 months
期刊介绍: The Journal of Bacteriology (JB) publishes research articles that probe fundamental processes in bacteria, archaea and their viruses, and the molecular mechanisms by which they interact with each other and with their hosts and their environments.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信