{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T10:24:22Z","timestamp":1785147862923,"version":"3.55.0"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,3,23]],"date-time":"2023-03-23T00:00:00Z","timestamp":1679529600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>Uropathogenic <jats:italic>Escherichia coli<\/jats:italic> is a major cause of urinary tract infections. Analysis of the innate immune response in immortalized urothelial cells suggests that the bacterial flagellar subunit, flagellin, is key in inducing host defenses. A panel of 48 clinical uro-associated <jats:italic>E<\/jats:italic>. <jats:italic>coli<\/jats:italic> isolates recovered from either cystitis, pyelonephritis asymptomatic bacteriuria (ABU) or UTI-associated bacteraemia infections were characterized for motility and their ability to induce an innate response in urothelial cells stably transfected with a NF-\u03baB luciferase reporter. Thirty-two isolates (67%) were identified as motile with strains recovered from cystitis patients exhibiting an uneven motility distribution pattern; seven of the cystitis isolates were associated with a\u2009 &amp;gt; 5-fold increase in NF-\u03baB signaling. To explore whether the NF-\u03baB signaling response reflected antigenic variation, flagellin was purified from 14 different isolates. Purified flagellin filaments generated comparable NF-\u03baB signaling responses, irrespective of either the source of the isolate or H-serotype. These data argued against any variability between isolates being related to flagellin itself. Investigations also argued that neither TLR4 dependent recognition of bacterial lipopolysaccharide nor growth fitness of the isolates played key roles in leading to the variable host response. To determine the roles, if any, of flagellar abundance in inducing these variable responses, flagellar hook numbers of a range of cystitis and ABU isolates were quantified. Images suggested that up to 60% of the isolate population exhibited flagella with the numbers averaging between 1 and 2 flagella per bacterial cell. These data suggest that selective pressures exist in the urinary tract that allow uro-associated <jats:italic>E<\/jats:italic>. <jats:italic>coli<\/jats:italic> strains to maintain motility, but exploit population heterogeneity, which together function to prevent host TLR5 recognition and bacterial killing.<\/jats:p>","DOI":"10.3389\/fmicb.2023.1093922","type":"journal-article","created":{"date-parts":[[2023,3,23]],"date-time":"2023-03-23T14:31:19Z","timestamp":1679581879000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Evasion of toll-like receptor recognition by Escherichia coli is mediated via population level regulation of flagellin production"],"prefix":"10.3389","volume":"14","author":[{"given":"Aaron","family":"Tan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qusai","family":"Alsenani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcello","family":"Lanz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Birchall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren K. 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Immunol."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"9247","DOI":"10.1073\/pnas.0502040102","article-title":"Evasion of toll-like receptor 5 by flagellated bacteria","volume":"102","author":"Andersen-Nissen","year":"2005","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref9","first-page":"99","article-title":"The coordination of flagellar gene expression and the flagellar assembly pathway","volume-title":"Pili and flagella: Current research and future trends","author":"Brown","year":"2009"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"13929","DOI":"10.1074\/jbc.R113.472274","article-title":"Programmed heterogeneity: epigenetic mechanisms in bacteria","volume":"288","author":"Casades\u00fas","year":"2013","journal-title":"J. Biol. 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Microbiol."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"eaaf1283","DOI":"10.1126\/scitranslmed.aaf1283","article-title":"Bacterial virulence phenotypes of Escherichia coli and host susceptibility determine risk for urinary tract infections","volume":"9","author":"Schreiber","year":"2017","journal-title":"Adv. Sci."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"41189","DOI":"10.1038\/srep41189","article-title":"Growth rate control of flagellar assembly in Escherichia coli strain RP437","volume":"7","author":"Sim","year":"2017","journal-title":"Sci. Rep."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"9748","DOI":"10.7554\/eLife.49748","article-title":"Genetically diverse uropathogenic Escherichia coli adopt a common transcriptional program in patients with UTIs","volume":"8","author":"Sintsova","year":"2019","journal-title":"elife"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"568","DOI":"10.1128\/IAI.01000-09","article-title":"Waging war against uropathogenic Escherichia coli: winning back the urinary tract","volume":"78","author":"Sivick","year":"2010","journal-title":"Infect. Immun."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"1084","DOI":"10.1016\/j.juro.2011.04.112","article-title":"Toll-like receptor responses of Normal human Urothelial cells to bacterial Flagellin and lipopolysaccharide","volume":"186","author":"Smith","year":"2011","journal-title":"J. Urol."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"6373","DOI":"10.1128\/IAI.72.11.6373-6381.2004","article-title":"Transcriptome of uropathogenic Escherichia coli during urinary tract infection","volume":"72","author":"Snyder","year":"2004","journal-title":"Infect. Immun."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"14966","DOI":"10.1073\/pnas.0900527106","article-title":"TLR4-mediated expulsion of bacteria from infected bladder epithelial cells","volume":"106","author":"Song","year":"2009","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1016\/S0168-6445(03)00064-0","article-title":"Regulation cascade of flagellar expression in gram-negative bacteria","volume":"27","author":"Soutourina","year":"2003","journal-title":"FEMS Microbiol. 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Microbiol."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"5780","DOI":"10.4049\/jimmunol.165.10.5780","article-title":"Toll-like receptor 4, but not toll-like receptor 2, is a signaling receptor for Escherichia and Salmonella lipopolysaccharides","volume":"165","author":"Tapping","year":"2000","journal-title":"J. Immunol."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1146\/annurev.micro.62.081307.163002","article-title":"Bistability, epigenetics, and bet-hedging in bacteria","volume":"62","author":"Veening","year":"2008","journal-title":"Annu. Rev. Microbiol."},{"key":"ref51","doi-asserted-by":"publisher","first-page":"1533","DOI":"10.1099\/mic.0.056036-0","article-title":"Functional and expressional analyses of the anti-FlhD4C2 factor gene ydiV in Escherichia coli","volume":"158","author":"Wada","year":"2012","journal-title":"Microbiology"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"798","DOI":"10.1016\/j.jmb.2005.11.020","article-title":"Structure of the Escherichia coli FlhDC complex, a prokaryotic heteromeric regulator of transcription","volume":"355","author":"Wang","year":"2006","journal-title":"J. Mol. Biol."},{"key":"ref53","doi-asserted-by":"publisher","first-page":"2936","DOI":"10.1128\/JB.185.9.2936-2943.2003","article-title":"Species-wide variation in the Escherichia coli flagellin (H-antigen) gene","volume":"185","author":"Wang","year":"2003","journal-title":"J. Bacteriol."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"17020","DOI":"10.1073\/pnas.252529799","article-title":"Extensive mosaic structure revealed by the complete genome sequence of uropathogenic Escherichia coli","volume":"99","author":"Welch","year":"2002","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref55","doi-asserted-by":"publisher","first-page":"7657","DOI":"10.1128\/IAI.73.11.7657-7668.2005","article-title":"Uropathogenic Escherichia coli flagella aid in efficient urinary tract colonization","volume":"73","author":"Wright","year":"2005","journal-title":"Infect. 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