{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T05:33:03Z","timestamp":1789623183272,"version":"build-2803163510"},"update-to":[{"DOI":"10.1371\/journal.ppat.1012483","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,9,13]],"date-time":"2024-09-13T00:00:00Z","timestamp":1726185600000}}],"reference-count":46,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2024,9,3]],"date-time":"2024-09-03T00:00:00Z","timestamp":1725321600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82220108006"],"award-info":[{"award-number":["82220108006"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82072321"],"award-info":[{"award-number":["82072321"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Fibronectin (FN) is an essential component of the extracellular matrix (ECM) that protects the integrity of the microvascular endothelial barrier (MEB). However, <jats:italic>Treponema pallidum subsp<\/jats:italic>. <jats:italic>pallidum<\/jats:italic> (<jats:italic>Tp<\/jats:italic>) breaches this barrier through elusive mechanisms and rapidly disseminates throughout the host. We aimed to understand the impact of <jats:italic>Tp<\/jats:italic> on the surrounding FN matrix of MEB and the underlying mechanisms of this effect. In this study, immunofluorescence assays (IF) were conducted to assess the integrity of the FN matrix surrounding human microvascular endothelial cell-1 (HMEC-1) with\/without <jats:italic>Tp<\/jats:italic> co-culture, revealing that only live <jats:italic>Tp<\/jats:italic> exhibited the capability to mediate FN matrix disaggregation in HMEC-1. Western blotting and IF were employed to determine the protein levels associated with the FN matrix during <jats:italic>Tp<\/jats:italic> infection, which showed the unaltered protein levels of total FN and its receptor integrin \u03b15\u03b21, along with reduced insoluble FN and increased soluble FN. Simultaneously, the integrin \u03b15\u03b21-binding protein\u2013intracellular vimentin maintained a stable total protein level while exhibiting an increase in the soluble form, specifically mediated by the phosphorylation of its 39<jats:sup>th<\/jats:sup> residue (pSer39-vimentin). Besides, this process of vimentin phosphorylation, which could be hindered by a serine-to-alanine mutation or inhibition of phosphorylated-AKT1 (pAKT1), promoted intracellular vimentin rearrangement and FN matrix disaggregation. Moreover, within the introduction of additional cellular FN rather than other <jats:italic>Tp<\/jats:italic>-adhered ECM protein, <jats:italic>in vitro<\/jats:italic> endothelial barrier traversal experiment and <jats:italic>in vivo<\/jats:italic> syphilitic infectivity test demonstrated that viable <jats:italic>Tp<\/jats:italic> was effectively prevented from penetrating the <jats:italic>in vitro<\/jats:italic> MEB or disseminating in <jats:italic>Tp<\/jats:italic>-challenged rabbits. This investigation revealed the active pAKT1\/pSer39-vimentin signal triggered by live <jats:italic>Tp<\/jats:italic> to expedite the disaggregation of the FN matrix and highlighted the importance of FN matrix stability in syphilis, thereby providing a novel perspective on ECM disruption mechanisms that facilitate <jats:italic>Tp<\/jats:italic> dissemination across the MEB.<\/jats:p>","DOI":"10.1371\/journal.ppat.1012483","type":"journal-article","created":{"date-parts":[[2024,9,3]],"date-time":"2024-09-03T17:38:46Z","timestamp":1725385126000},"page":"e1012483","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Phosphorylated vimentin-triggered fibronectin matrix disaggregation enhances the dissemination of Treponema pallidum subsp. pallidum across the microvascular endothelial barrier"],"prefix":"10.1371","volume":"20","author":[{"given":"Xi","family":"Luo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Litian","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyuan","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liyan","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanqiang","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinbo","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wujian","family":"Ke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7155-6079","authenticated-orcid":true,"given":"Bin","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,9,3]]},"reference":[{"key":"ppat.1012483.ref001","doi-asserted-by":"crossref","first-page":"17073","DOI":"10.1038\/nrdp.2017.73","article-title":"Syphilis","volume":"3","author":"RW Peeling","year":"2017","journal-title":"Nature reviews Disease primers"},{"issue":"1","key":"ppat.1012483.ref002","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1080\/09273948.2017.1371765","article-title":"Ocular Syphilis: An Update","volume":"27","author":"P Dutta Majumder","year":"2019","journal-title":"Ocular immunology and inflammation"},{"issue":"12","key":"ppat.1012483.ref003","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1016\/S0828-282X(08)70712-8","article-title":"Cardiovascular syphilis","volume":"24","author":"J. Morphet","year":"2008","journal-title":"The Canadian journal of cardiology"},{"issue":"3","key":"ppat.1012483.ref004","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/j.bjid.2016.01.007","article-title":"Tertiary syphilis: tubero-serpiginous and tubero-ulcerous syphilids","volume":"20","author":"LM Jorge","year":"2016","journal-title":"The Brazilian journal of infectious diseases: an official publication of the Brazilian Society of Infectious Diseases"},{"issue":"6","key":"ppat.1012483.ref005","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1001\/archderm.1937.01470240093008","article-title":"RAPIDITY WITH WHICH SPIROCHAETA PALLIDA INVADES THE BLOOD STREAM","volume":"35","author":"GW RAIZISS","year":"1937","journal-title":"Archives of Dermatology and Syphilology"},{"key":"ppat.1012483.ref006","doi-asserted-by":"crossref","first-page":"691731","DOI":"10.3389\/fmicb.2021.691731","article-title":"Treponema pallidum Disrupts VE-Cadherin Intercellular Junctions and Traverses Endothelial Barriers Using a Cholesterol-Dependent Mechanism","volume":"12","author":"KV Lithgow","year":"2021","journal-title":"Frontiers in microbiology"},{"key":"ppat.1012483.ref007","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.crmicr.2020.08.001","article-title":"Streptococcus pneumoniae utilizes a novel dynamin independent pathway for entry and persistence in brain endothelium","volume":"1","author":"MV Surve","year":"2020","journal-title":"Current research in microbial sciences"},{"issue":"7","key":"ppat.1012483.ref008","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1007\/s10571-018-0609-2","article-title":"Mechanisms of Blood Brain Barrier Disruption by Different Types of Bacteria, and Bacterial-Host Interactions Facilitate the Bacterial Pathogen Invading the Brain","volume":"38","author":"MMJ Al-Obaidi","year":"2018","journal-title":"Cellular and molecular 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An in vitro model","volume":"45","author":"FW Chandler","year":"1969","journal-title":"The British journal of venereal diseases"},{"issue":"3","key":"ppat.1012483.ref028","doi-asserted-by":"crossref","DOI":"10.1128\/mBio.01153-18","article-title":"Long-Term In Vitro Culture of the Syphilis Spirochete Treponema pallidum subsp. pallidum","volume":"9","author":"DG Edmondson","year":"2018","journal-title":"mBio"},{"key":"ppat.1012483.ref029","doi-asserted-by":"crossref","first-page":"857727","DOI":"10.3389\/fimmu.2022.857727","article-title":"YTHDF1 Negatively Regulates Treponema pallidum-Induced Inflammation in THP-1 Macrophages by Promoting SOCS3 Translation in an m6A-Dependent Manner","volume":"13","author":"Z Li","year":"2022","journal-title":"Frontiers in immunology"},{"key":"ppat.1012483.ref030","article-title":"Analysis of fibronectin matrix assembly","author":"I Wierzbicka-Patynowski","year":"2004","journal-title":"Current protocols in cell 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Luthra","year":"2020","journal-title":"PLoS pathogens"},{"key":"ppat.1012483.ref034","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1146\/annurev-cellbio-100109-104020","article-title":"Assembly of fibronectin extracellular matrix","volume":"26","author":"P Singh","year":"2010","journal-title":"Annual review of cell and developmental biology"},{"issue":"W1","key":"ppat.1012483.ref035","doi-asserted-by":"crossref","first-page":"W243","DOI":"10.1093\/nar\/gkad383","article-title":"GPS 6.0: an updated server for prediction of kinase-specific phosphorylation sites in proteins","volume":"51","author":"M Chen","year":"2023","journal-title":"Nucleic acids research"},{"key":"ppat.1012483.ref036","doi-asserted-by":"crossref","first-page":"437","DOI":"10.3389\/fmicb.2018.00437","article-title":"Group B Streptococcal Colonization, Molecular Characteristics, and Epidemiology","volume":"9","author":"S Shabayek","year":"2018","journal-title":"Frontiers in microbiology"},{"issue":"Pt 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Speziale","year":"2020","journal-title":"Frontiers in microbiology"},{"issue":"5","key":"ppat.1012483.ref040","doi-asserted-by":"crossref","first-page":"e0106221","DOI":"10.1128\/mBio.01062-21","article-title":"More Is Not Always Better-the Double-Headed Role of Fibronectin in Staphylococcus aureus Host Cell Invasion","volume":"12","author":"S Niemann","year":"2021","journal-title":"mBio"},{"issue":"1","key":"ppat.1012483.ref041","doi-asserted-by":"crossref","first-page":"1538","DOI":"10.1038\/s41598-017-01589-4","article-title":"Identification of Tp0751 (Pallilysin) as a Treponema pallidum Vascular Adhesin by Heterologous Expression in the Lyme disease Spirochete","volume":"7","author":"WA Kao","year":"2017","journal-title":"Sci Rep"},{"issue":"9","key":"ppat.1012483.ref042","doi-asserted-by":"crossref","first-page":"e1005919","DOI":"10.1371\/journal.ppat.1005919","article-title":"The Structure of Treponema pallidum Tp0751 (Pallilysin) Reveals a Non-canonical Lipocalin Fold That 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