{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T17:25:31Z","timestamp":1778261131227,"version":"3.51.4"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,10,26]],"date-time":"2023-10-26T00:00:00Z","timestamp":1698278400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32200025"],"award-info":[{"award-number":["32200025"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>The Gram-negative opportunistic pathogen <jats:italic>Pseudomonas aeruginosa<\/jats:italic> possesses hierarchical quorum sensing (QS) systems. The intricate QS network of <jats:italic>P. aeruginosa<\/jats:italic> synchronizes a suite of virulence factors, contributing to the mortality and morbidity linked to the pathogenicity of this bacterium. Previous studies have revealed that variations in the <jats:italic>lasR<\/jats:italic> gene are frequently observed in chronic isolates of cystic fibrosis (CF). Specifically, LasR<jats:sup>Q45stop<\/jats:sup> was identified as a common variant among CF, <jats:italic>lasR<\/jats:italic> mutants during statistical analysis of the clinical <jats:italic>lasR<\/jats:italic> mutants in the database. In this study, we introduced LasR<jats:sup>Q45stop<\/jats:sup> into the chromosome of <jats:italic>P. aeruginosa<\/jats:italic> PAO1 through allelic replacement. The social traits of PAO1 LasR<jats:sup>Q45stop<\/jats:sup> were found to be equivalent to those of PAO1 LasR-null isolates. By co-evolving with the wild-type in caseinate broth, elastase-phenotypic-variability variants were derived from the LasR<jats:sup>Q45stop<\/jats:sup> subpopulation. Upon further examination of four LasR<jats:sup>Q45stop<\/jats:sup> sublines, we determined that the variation of T2SS-peptidase <jats:italic>xcpA<\/jats:italic> and <jats:italic>mexT<\/jats:italic> genes plays a pivotal role in the divergence of various phenotypes, including public goods elastase secretion and other pathogenicity traits. Furthermore, XcpA mutants demonstrated a fitness advantage compared to parent strains during co-evolution. Numerous phenotypic variations were associated with subline-specific genetic alterations. Collectively, these findings suggest that even within the same parental subline, there is ongoing microevolution of individual mutational trajectory diversity during adaptation.<\/jats:p>","DOI":"10.3389\/fmicb.2023.1256785","type":"journal-article","created":{"date-parts":[[2023,10,26]],"date-time":"2023-10-26T14:37:11Z","timestamp":1698331031000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["T2SS-peptidase XcpA associated with LasR evolutional phenotypic variations provides a fitness advantage to Pseudomonas aeruginosa PAO1"],"prefix":"10.3389","volume":"14","author":[{"given":"Mengmeng","family":"Cheng","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruiyi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisheng","family":"Liao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,10,26]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"3521","DOI":"10.1007\/s00253-019-09618-0","article-title":"Natural quorum sensing inhibitors effectively downregulate gene expression of Pseudomonas aeruginosa virulence factors","volume":"103","author":"Ahmed","year":"2019","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1734","DOI":"10.1038\/ismej.2014.259","article-title":"Non-social adaptation defers a tragedy of the commons in Pseudomonas aeruginosa quorum sensing","volume":"9","author":"Asfahl","year":"2015","journal-title":"ISME J."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"1339","DOI":"10.1046\/j.1365-2958.2003.03758.x","article-title":"Cleavage of preflagellins by an aspartic acid signal peptidase is essential for flagellation in the archaeon Methanococcus voltae","volume":"50","author":"Bardy","year":"2003","journal-title":"Mol. Microbiol."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"534","DOI":"10.1016\/j.ijmm.2010.08.005","article-title":"Protein secretion systems in Pseudomonas aeruginosa: a wealth of pathogenic weapons","volume":"300","author":"Bleves","year":"2010","journal-title":"Int. J. Med. Microbiol."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"7021","DOI":"10.1073\/pnas.1819801116","article-title":"Social cheating in a Pseudomonas aeruginosa quorum-sensing variant","volume":"116","author":"Chen","year":"2019","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1038\/nmeth765","article-title":"A Tn7-based broad-range bacterial cloning and expression system","volume":"2","author":"Choi","year":"2005","journal-title":"Nat. Methods"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"E2823","DOI":"10.1073\/pnas.1214128109","article-title":"Strain-dependent diversity in the Pseudomonas aeruginosa quorum-sensing regulon","volume":"109","author":"Chugani","year":"2012","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1111\/j.1365-2958.1995.tb02267.x","article-title":"ComC is required for the processing and translocation of ComGC, a pilin-like competence protein of Bacillus subtilis","volume":"15","author":"Chung","year":"1995","journal-title":"Mol. Microbiol."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"e00532","DOI":"10.1128\/mBio.00532-20","article-title":"RhlR-regulated acyl-Homoserine lactone quorum sensing in a cystic fibrosis isolate of Pseudomonas aeruginosa","volume":"11","author":"Cruz","year":"2020","journal-title":"mBio"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1038\/nature06279","article-title":"Cooperation and conflict in quorum-sensing bacterial populations","volume":"450","author":"Diggle","year":"2007","journal-title":"Nature"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"88","DOI":"10.4161\/cib.1.1.6717","article-title":"A novel two-component system BqsS-BqsR modulates quorum sensing-dependent biofilm decay in Pseudomonas aeruginosa","volume":"1","author":"Dong","year":"2008","journal-title":"Commun. Integr. Biol."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"e01513","DOI":"10.1128\/mBio.01513-16","article-title":"LasR variant cystic fibrosis isolates reveal an adaptable quorum-sensing hierarchy in Pseudomonas aeruginosa","volume":"7","author":"Feltner","year":"2016","journal-title":"mBio"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"10190","DOI":"10.1038\/s41598-019-46651-5","article-title":"Dynamics of cheater invasion in a cooperating population of Pseudomonas aeruginosa","volume":"9","author":"Feng","year":"2019","journal-title":"Sci. Rep."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1016\/j.bbamcr.2004.05.003","article-title":"The underlying mechanisms of type II protein secretion","volume":"1694","author":"Filloux","year":"2004","journal-title":"Biochim. Biophys. Acta"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"155","DOI":"10.3389\/fmicb.2011.00155","article-title":"Protein secretion systems in Pseudomonas aeruginosa: an essay on diversity, evolution, and function","volume":"2","author":"Filloux","year":"2011","journal-title":"Front. Microbiol."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"841","DOI":"10.1038\/nrmicro2907","article-title":"Adaptation of Pseudomonas aeruginosa to the cystic fibrosis airway: an evolutionary perspective","volume":"10","author":"Folkesson","year":"2012","journal-title":"Nat. Rev. Microbiol."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"1820","DOI":"10.1038\/nprot.2015.115","article-title":"Precision-engineering the Pseudomonas aeruginosa genome with two-step allelic exchange","volume":"10","author":"Hmelo","year":"2015","journal-title":"Nat. Protoc."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1016\/j.ijmm.2010.08.008","article-title":"Adaptation of Pseudomonas aeruginosa during persistence in the cystic fibrosis lung","volume":"300","author":"Hogardt","year":"2010","journal-title":"Int. J. Med. Microbiol."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"2931","DOI":"10.1038\/s41467-019-10778-w","article-title":"An integrated genomic regulatory network of virulence-related transcriptional factors in Pseudomonas aeruginosa","volume":"10","author":"Huang","year":"2019","journal-title":"Nat. Commun."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"e1009681","DOI":"10.1371\/journal.ppat.1009681","article-title":"Genome-wide association study of signature genetic alterations among Pseudomonas aeruginosa cystic fibrosis isolates","volume":"17","author":"Hwang","year":"2021","journal-title":"PLoS Pathog."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"4912","DOI":"10.1128\/JB.184.17.4912-4919.2002","article-title":"LasR, a transcriptional activator of Pseudomonas aeruginosa virulence genes, functions as a multimer","volume":"184","author":"Kiratisin","year":"2002","journal-title":"J. Bacteriol."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"2262","DOI":"10.1128\/IAI.73.4.2262-2272.2005","article-title":"Virulence of Pseudomonas aeruginosa in a murine model of gastrointestinal colonization and dissemination in neutropenia","volume":"73","author":"Koh","year":"2005","journal-title":"Infect. Immun."},{"key":"ref23","doi-asserted-by":"publisher","DOI":"10.1128\/ecosalplus.ESP-0034-2018","article-title":"Architecture, function, and substrates of the type II secretion system","volume":"8","author":"Korotkov","year":"2019","journal-title":"EcoSal Plus"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"7027","DOI":"10.1073\/pnas.1819796116","article-title":"Evolution of the Pseudomonas aeruginosa quorum-sensing hierarchy","volume":"116","author":"Kostylev","year":"2019","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"1502","DOI":"10.1074\/jbc.275.2.1502","article-title":"The type 4 prepilin peptidases comprise a novel family of aspartic acid proteases","volume":"275","author":"LaPointe","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"19635","DOI":"10.1074\/jbc.RA119.011047","article-title":"Quorum sensing-dependent post-secretional activation of extracellular proteases in Pseudomonas aeruginosa","volume":"294","author":"Li","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"821895","DOI":"10.3389\/fmicb.2022.821895","article-title":"Microevolution of the mexT and lasR reinforces the bias of quorum sensing system in laboratory strains of Pseudomonas aeruginosa PAO1","volume":"13","author":"Liu","year":"2022","journal-title":"Front. Microbiol."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"1017707","DOI":"10.3389\/fmicb.2022.1017707","article-title":"Quorum sensing regulates heteroresistance in Pseudomonas aeruginosa","volume":"13","author":"Lu","year":"2022","journal-title":"Front. Microbiol."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"1051","DOI":"10.1016\/s1286-4579(00)01259-4","article-title":"Establishment of Pseudomonas aeruginosa infection: lessons from a versatile opportunist","volume":"2","author":"Lyczak","year":"2000","journal-title":"Microbes Infect."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"39","DOI":"10.3389\/fcimb.2017.00039","article-title":"Pseudomonas aeruginosa lifestyle: a paradigm for adaptation, survival, and persistence","volume":"7","author":"Moradali","year":"2017","journal-title":"Front. Cell Infect. Microbiol."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"17981","DOI":"10.1073\/pnas.1316981110","article-title":"A quorum-sensing inhibitor blocks Pseudomonas aeruginosa virulence and biofilm formation","volume":"110","author":"O\u2019Loughlin","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1038\/s41392-022-01056-1","article-title":"Pseudomonas aeruginosa: pathogenesis, virulence factors, antibiotic resistance, interaction with host, technology advances and emerging therapeutics","volume":"7","author":"Qin","year":"2022","journal-title":"Signal Transduct. Target Ther."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"15876","DOI":"10.1073\/pnas.0705653104","article-title":"Social cheating in Pseudomonas aeruginosa quorum sensing","volume":"104","author":"Sandoz","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1146\/annurev-micro-092412-155635","article-title":"Acyl-Homoserine lactone quorum sensing: from evolution to application","volume":"67","author":"Schuster","year":"2013","journal-title":"Annu. Rev. Microbiol."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"2066","DOI":"10.1128\/JB.185.7.2066-2079.2003","article-title":"Identification, timing, and signal specificity of Pseudomonas aeruginosa quorum-controlled genes: a transcriptome analysis","volume":"185","author":"Schuster","year":"2003","journal-title":"J. Bacteriol."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"654","DOI":"10.1128\/jb.177.3.654-659.1995","article-title":"Activation of the Pseudomonas aeruginosa lasI gene by LasR and the Pseudomonas autoinducer PAI: an autoinduction regulatory hierarchy","volume":"177","author":"Seed","year":"1995","journal-title":"J. Bacteriol."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"959","DOI":"10.1038\/35023079","article-title":"Complete genome sequence of Pseudomonas aeruginosa PAO1, an opportunistic pathogen","volume":"406","author":"Stover","year":"2000","journal-title":"Nature"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"688","DOI":"10.1016\/j.bbrc.2019.04.055","article-title":"Identification of a potent inhibitor of type II secretion system from Pseudomonas aeruginosa","volume":"513","author":"Swietnicki","year":"2019","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1264\/jsme2.me12167","article-title":"Interspecies interaction between Pseudomonas aeruginosa and other microorganisms","volume":"28","author":"Tashiro","year":"2013","journal-title":"Microbes Environ."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1080\/17476348.2021.1906225","article-title":"Pseudomonas aeruginosa in bronchiectasis: infection, inflammation, and therapies","volume":"15","author":"Vidaillac","year":"2021","journal-title":"Expert Rev. Resp. Med."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"13344","DOI":"10.1038\/s41598-018-30813-y","article-title":"Characterization of lasR-deficient clinical isolates of Pseudomonas aeruginosa","volume":"8","author":"Wang","year":"2018","journal-title":"Sci. Rep."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"2187","DOI":"10.1073\/pnas.1500704112","article-title":"Quorum sensing and policing of Pseudomonas aeruginosa social cheaters","volume":"112","author":"Wang","year":"2015","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"2184","DOI":"10.1099\/mic.0.2008\/019281-0","article-title":"Role of quorum sensing by Pseudomonas aeruginosa in microbial keratitis and cystic fibrosis","volume":"154","author":"Willcox","year":"2008","journal-title":"Microbiology"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"1689","DOI":"10.1111\/j.1365-2958.2006.05462.x","article-title":"MvfR, a key Pseudomonas aeruginosa pathogenicity LTTR-class regulatory protein, has dual ligands","volume":"62","author":"Xiao","year":"2006","journal-title":"Mol. Microbiol."}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2023.1256785\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,26]],"date-time":"2023-10-26T14:37:14Z","timestamp":1698331034000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2023.1256785\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,26]]},"references-count":44,"alternative-id":["10.3389\/fmicb.2023.1256785"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2023.1256785","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,26]]},"article-number":"1256785"}}