{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T01:16:19Z","timestamp":1790298979997,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1011752","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,12,7]],"date-time":"2023-12-07T00:00:00Z","timestamp":1701907200000}}],"reference-count":107,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2023,11,27]],"date-time":"2023-11-27T00:00:00Z","timestamp":1701043200000},"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":["AI078958"],"award-info":[{"award-number":["AI078958"]}],"id":[{"id":"10.13039\/100015691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015691","name":"Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI148844"],"award-info":[{"award-number":["AI148844"]}],"id":[{"id":"10.13039\/100015691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35122535"],"award-info":[{"award-number":["R35122535"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015691","name":"Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI045801"],"award-info":[{"award-number":["AI045801"]}],"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>As an enzootic pathogen, the Lyme disease bacterium <jats:italic>Borrelia burgdorferi<\/jats:italic> possesses multiple copies of chemotaxis proteins, including two chemotaxis histidine kinases (CHK), CheA<jats:sub>1<\/jats:sub> and CheA<jats:sub>2<\/jats:sub>. Our previous study showed that CheA<jats:sub>2<\/jats:sub> is a genuine CHK that is required for chemotaxis; however, the role of CheA<jats:sub>1<\/jats:sub> remains mysterious. This report first compares the structural features that differentiate CheA<jats:sub>1<\/jats:sub> and CheA<jats:sub>2<\/jats:sub> and then provides evidence to show that CheA<jats:sub>1<\/jats:sub> is an atypical CHK that controls the virulence of <jats:italic>B<\/jats:italic>. <jats:italic>burgdorferi<\/jats:italic> through modulating the stability of RpoS, a key transcriptional regulator of the spirochete. First, microscopic analyses using green-fluorescence-protein (GFP) tags reveal that CheA<jats:sub>1<\/jats:sub> has a unique and dynamic cellular localization. Second, loss-of-function studies indicate that CheA<jats:sub>1<\/jats:sub> is not required for chemotaxis <jats:italic>in vitro<\/jats:italic> despite sharing a high sequence and structural similarity to its counterparts from other bacteria. Third, mouse infection studies using needle inoculations show that a deletion mutant of CheA<jats:sub>1<\/jats:sub> (<jats:italic>cheA<\/jats:italic><jats:sub><jats:italic>1<\/jats:italic><\/jats:sub><jats:sup><jats:italic>mut<\/jats:italic><\/jats:sup>) is able to establish systemic infection in immune-deficient mice but fails to do so in immune-competent mice albeit the mutant can survive at the inoculation site for up to 28 days. Tick and mouse infection studies further demonstrate that CheA<jats:sub>1<\/jats:sub> is dispensable for tick colonization and acquisition but essential for tick transmission. Lastly, mechanistic studies combining immunoblotting, protein turnover, mutagenesis, and RNA-seq analyses reveal that depletion of CheA<jats:sub>1<\/jats:sub> affects RpoS stability, leading to reduced expression of several RpoS-regulated virulence factors (i.e., OspC, BBK32, and DbpA), likely due to dysregulated <jats:italic>clpX<\/jats:italic> and <jats:italic>lon<\/jats:italic> protease expression. Bulk RNA-seq analysis of infected mouse skin tissues further show that <jats:italic>cheA<\/jats:italic><jats:sub><jats:italic>1<\/jats:italic><\/jats:sub><jats:sup><jats:italic>mut<\/jats:italic><\/jats:sup> fails to elicit mouse <jats:italic>tnf-\u03b1<\/jats:italic>, <jats:italic>il-10<\/jats:italic>, <jats:italic>il-1\u03b2<\/jats:italic>, and <jats:italic>ccl2<\/jats:italic> expression, four important cytokines for Lyme disease development and <jats:italic>B<\/jats:italic>. <jats:italic>burgdorferi<\/jats:italic> transmigration. Collectively, these results reveal a unique role and regulatory mechanism of CheA<jats:sub>1<\/jats:sub> in modulating virulence factor expression and add new insights into understanding the regulatory network of <jats:italic>B<\/jats:italic>. <jats:italic>burgdorferi<\/jats:italic>.<\/jats:p>","DOI":"10.1371\/journal.ppat.1011752","type":"journal-article","created":{"date-parts":[[2023,11,27]],"date-time":"2023-11-27T19:21:25Z","timestamp":1701112885000},"page":"e1011752","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":13,"title":["A chemosensory-like histidine kinase is dispensable for chemotaxis in vitro but regulates the virulence of Borrelia burgdorferi through modulating the stability of RpoS"],"prefix":"10.1371","volume":"19","author":[{"given":"Ching Wooen","family":"Sze","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Lynch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radha","family":"Iyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian R.","family":"Crane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ira","family":"Schwartz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1872-4870","authenticated-orcid":true,"given":"Chunhao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,11,27]]},"reference":[{"issue":"12","key":"ppat.1011752.ref001","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1038\/nrm1524","article-title":"Making sense of it all: bacterial chemotaxis","volume":"5","author":"GH Wadhams","year":"2004","journal-title":"Nat Rev Mol Cell Biol"},{"key":"ppat.1011752.ref002","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1146\/annurev.cellbio.13.1.457","article-title":"The two-component signaling pathway of bacterial chemotaxis: a 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