{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T12:28:34Z","timestamp":1790166514138,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1012871","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T00:00:00Z","timestamp":1737590400000}}],"reference-count":72,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T00:00:00Z","timestamp":1736467200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100015691","name":"Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R21 AI133158"],"award-info":[{"award-number":["R21 AI133158"]}],"id":[{"id":"10.13039\/100015691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Host-pathogen interactions represent a dynamic evolutionary process, wherein both hosts and pathogens continuously develop complex mechanisms to outmaneuver each other. <jats:italic>Borrelia burgdorferi<\/jats:italic>, the Lyme disease pathogen, has evolved an intricate antigenic variation mechanism to evade the host immune response, enabling its dissemination, persistence, and pathogenicity. Despite the discovery of this mechanism over two decades ago, the precise processes, genetic elements, and proteins involved in this system remain largely unknown. The <jats:italic>vls<\/jats:italic> locus, which is the site of antigenic variation, has been notoriously challenging to manipulate genetically due to its highly conserved structural features, even with significant advancements in molecular biology and genetic engineering for this highly segmented pathogen. Our study highlights the pivotal role of plasmid topology in facilitating <jats:italic>in trans<\/jats:italic> gene recombination. We demonstrate that gene conversion can occur <jats:italic>in trans<\/jats:italic> when a copy of <jats:italic>vlsE<\/jats:italic> gene is present on a linear plasmid, contrary to previous observations suggesting a <jats:italic>cis<\/jats:italic> arrangement is required for <jats:italic>vlsE<\/jats:italic> recombination. Significantly, employing this <jats:italic>in trans<\/jats:italic> gene conversion strategy with a linear plasmid, we have, for the first time, achieved targeted genetic mutation of putative <jats:italic>cis<\/jats:italic>-acting elements in the native <jats:italic>vlsE<\/jats:italic> gene. This has unveiled a potentially crucial role for the 17 bp direct repeats that flank the central variable cassette region of <jats:italic>vlsE<\/jats:italic>. Furthermore, we validated the reliability and reproducibility of our mutational approach by successfully inserting stop codons at two distinct sites within the central variable cassette of <jats:italic>vlsE<\/jats:italic>. Thus, this study presents a significant methodological innovation enabling the direct manipulation of the <jats:italic>vls<\/jats:italic> locus and lays the groundwork for systematic exploration of specific mutations affecting the mechanism of antigenic variation. As a result, it creates new avenues for research and raises intriguing questions that could guide the development of novel methods to explore host-pathogen interactions of the agent of Lyme disease.<\/jats:p>","DOI":"10.1371\/journal.ppat.1012871","type":"journal-article","created":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T20:16:39Z","timestamp":1736540199000},"page":"e1012871","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Breaking a barrier: In trans vlsE recombination and genetic manipulation of the native vlsE gene of the Lyme disease pathogen"],"prefix":"10.1371","volume":"21","author":[{"given":"Preeti","family":"Singh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4336-0298","authenticated-orcid":true,"given":"Troy","family":"Bankhead","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,1,10]]},"reference":[{"key":"ppat.1012871.ref001","doi-asserted-by":"crossref","first-page":"16090","DOI":"10.1038\/nrdp.2016.90","article-title":"Lyme borreliosis.","volume":"2","author":"AC Steere","year":"2016","journal-title":"Nat Rev Dis Primers"},{"issue":"3","key":"ppat.1012871.ref002","doi-asserted-by":"crossref","first-page":"e0120548","DOI":"10.1371\/journal.pone.0120548","article-title":"Complete genome sequence of Borrelia afzelii K78 and comparative genome analysis.","volume":"10","author":"W Sch\u00fcler","year":"2015","journal-title":"PLoS 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