{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T11:22:53Z","timestamp":1789730573885,"version":"4.0.1"},"update-to":[{"DOI":"10.1371\/journal.ppat.1014256","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000}}],"reference-count":56,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T00:00:00Z","timestamp":1779753600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004328","name":"Genentech","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004328","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Outer membrane vesicles (OMVs) are nanoscale proteoliposomes shed by Gram-negative bacteria that mediate host-pathogen interactions and hold promise as platforms for vaccines and targeted drug delivery. Despite their biological and translational significance, the cellular mechanisms governing OMV entry into host cells remain poorly understood. Here, we demonstrate that\n                    <jats:italic>E. coli<\/jats:italic>\n                    OMVs are internalized by epithelial cells via clathrin-mediated, receptor-dependent endocytosis. Using a high-throughput screen of over 1,500 human single-pass transmembrane proteins, we identify T-cell immunoglobulin and mucin-domain 1 (TIM-1) as a strong OMV-binding receptor. Functional validation revealed that TIM-1 overexpression markedly increased OMV uptake, whereas TIM-1 knockout and antibody-mediated blockade significantly impaired internalization across multiple cell lines. Mechanistic studies demonstrate that TIM-1 binds to lipopolysaccharide (LPS) on the OMV surface via its phosphatidylserine-binding domain. Uptake of OMVs by TIM-1 triggers proinflammatory cytokine production which can be reduced by preventing this interaction. Additionally, OMVs from multiple bacterial species hijack TIM-1 for entry, making it an intriguing antivirulence strategy. Our findings establish TIM-1 as a critical host receptor mediating OMV uptake and provide a novel approach to modulate vesicle-driven pathogenesis and enhance OMV-based therapies.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1014256","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T17:40:47Z","timestamp":1779817247000},"page":"e1014256","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Outer membrane vesicles hijack TIM-1 for cellular uptake"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3558-438X","authenticated-orcid":true,"given":"Craig R.","family":"MacNair","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Varnesh","family":"Tiku","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengya","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariana D.","family":"Sanchez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barath","family":"Udayasuryan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina Theresa","family":"Kroll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adarsh","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7748-212X","authenticated-orcid":true,"given":"Man-Wah","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,5,26]]},"reference":[{"issue":"10","key":"ppat.1014256.ref001","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1038\/nrmicro3525","article-title":"Outer-membrane vesicles from Gram-negative bacteria: biogenesis and functions","volume":"13","author":"C Schwechheimer","year":"2015","journal-title":"Nat Rev Microbiol"},{"issue":"7","key":"ppat.1014256.ref002","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1038\/s41579-023-00875-5","article-title":"Composition and 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Uptake of released toxin and vesicles by gastric epithelium","volume":"188","author":"R Fiocca","year":"1999","journal-title":"J Pathol"},{"issue":"6","key":"ppat.1014256.ref018","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.3201\/eid2206.151093","article-title":"Ecologic study of meningococcal B vaccine and Neisseria gonorrhoeae infection, Norway","volume":"22","author":"J Whelan","year":"2016","journal-title":"Emerg Infect Dis"},{"key":"ppat.1014256.ref019","doi-asserted-by":"crossref","DOI":"10.1093\/ofid\/ofx180.002","article-title":"Possible Impact of wide-scale vaccination against Serogroup B neisseria meningitidis on gonorrhea incidence rates in one region of Quebec, Canada","volume":"4","author":"J Longtin","year":"2017","journal-title":"Open Forum Infectious Diseases"},{"issue":"7","key":"ppat.1014256.ref020","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1016\/S1473-3099(21)00812-4","article-title":"Effectiveness of a serogroup B outer membrane 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Manangeeswaran","year":"2012","journal-title":"Gastroenterology"},{"issue":"6","key":"ppat.1014256.ref039","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1016\/j.immuni.2007.11.011","article-title":"TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells","volume":"27","author":"N Kobayashi","year":"2007","journal-title":"Immunity"},{"issue":"3","key":"ppat.1014256.ref040","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1128\/jb.95.3.833-843.1968","article-title":"Lipids of Salmonella typhimurium and Escherichia coli: structure and metabolism","volume":"95","author":"GF Ames","year":"1968","journal-title":"J Bacteriol"},{"issue":"11","key":"ppat.1014256.ref041","doi-asserted-by":"crossref","DOI":"10.1128\/jvi.01649-24","article-title":"The ability of human TIM1 to bind phosphatidylethanolamine enhances viral uptake and efferocytosis compared to rhesus and mouse orthologs","volume":"98","author":"L Zhang","year":"2024","journal-title":"J Virol"},{"issue":"1","key":"ppat.1014256.ref042","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/s41579-018-0112-2","article-title":"Types and origins of bacterial membrane vesicles","volume":"17","author":"M Toyofuku","year":"2019","journal-title":"Nat Rev Microbiol"},{"issue":"5917","key":"ppat.1014256.ref043","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1038\/303526a0","article-title":"Sensitization of Gram-negative bacteria to antibiotics and complement by a nontoxic oligopeptide","volume":"303","author":"M Vaara","year":"1983","journal-title":"Nature"},{"key":"ppat.1014256.ref044","doi-asserted-by":"crossref","first-page":"1845","DOI":"10.1529\/biophysj.104.047944","article-title":"Temperature dependence of the binding of endotoxins to the polycationic peptides polymyxin B and its nonapeptide","volume":"88","author":"K Brandenburg","year":"2005","journal-title":"Biophys 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