{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T23:45:47Z","timestamp":1769298347700,"version":"3.49.0"},"reference-count":31,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2016,8,3]],"date-time":"2016-08-03T00:00:00Z","timestamp":1470182400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"UK Ministry of Defence"},{"name":"Medical Research Council UK","award":["G0900453"],"award-info":[{"award-number":["G0900453"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>The bronchial epithelium provides protection against pathogens from the inhaled environment through the formation of a highly-regulated barrier. In order to understand the pulmonary diseases melioidosis and tularemia caused by Burkholderia thailandensis and Fransicella tularensis, respectively, the barrier function of the human bronchial epithelium were analysed. Polarised 16HBE14o- or differentiated primary human bronchial epithelial cells (BECs) were exposed to increasing multiplicities of infection (MOI) of B. thailandensis or F. tularensis Live Vaccine Strain and barrier responses monitored over 24\u201372 h. Challenge of polarized BECs with either bacterial species caused an MOI- and time-dependent increase in ionic permeability, disruption of tight junctions, and bacterial passage from the apical to the basolateral compartment. B. thailandensis was found to be more invasive than F. tularensis. Both bacterial species induced an MOI-dependent increase in TNF-\u03b1 release. An increase in ionic permeability and TNF-\u03b1 release was induced by B. thailandensis in differentiated BECs. Pretreatment of polarised BECs with the corticosteroid fluticasone propionate reduced bacterial-dependent increases in ionic permeability, bacterial passage, and TNF-\u03b1 release. TNF blocking antibody Enbrel\u00ae reduced bacterial passage only. BEC barrier properties are disrupted during respiratory bacterial infections and targeting with corticosteroids or anti-TNF compounds may represent a therapeutic option.<\/jats:p>","DOI":"10.3390\/pathogens5030053","type":"journal-article","created":{"date-parts":[[2016,8,3]],"date-time":"2016-08-03T10:10:31Z","timestamp":1470219031000},"page":"53","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Modulation of Human Airway Barrier Functions during Burkholderia thailandensis and Francisella tularensis Infection"],"prefix":"10.3390","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6133-7318","authenticated-orcid":false,"given":"Cornelia","family":"Blume","sequence":"first","affiliation":[{"name":"Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan","family":"David","sequence":"additional","affiliation":[{"name":"Defence Science and Technology Laboratory (Dstl), Porton Down, Salisbury SP4 0JQ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachel","family":"Bell","sequence":"additional","affiliation":[{"name":"Defence Science and Technology Laboratory (Dstl), Porton Down, Salisbury SP4 0JQ, UK"},{"name":"Centre for Molecular and Cellular Biology of Inflammation, Guy\u2019s Campus, King\u2019s College London, London SE1 1UL, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jay","family":"Laver","sequence":"additional","affiliation":[{"name":"Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4297-6728","authenticated-orcid":false,"given":"Robert","family":"Read","sequence":"additional","affiliation":[{"name":"Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK"},{"name":"Southampton NIHR Respiratory Biomedical Research Unit, University Hospital Southampton, Southampton SO16 6YD, UK"},{"name":"Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Graeme","family":"Clark","sequence":"additional","affiliation":[{"name":"Defence Science and Technology Laboratory (Dstl), Porton Down, Salisbury SP4 0JQ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Donna","family":"Davies","sequence":"additional","affiliation":[{"name":"Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK"},{"name":"Southampton NIHR Respiratory Biomedical Research Unit, University Hospital Southampton, Southampton SO16 6YD, UK"},{"name":"Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily","family":"Swindle","sequence":"additional","affiliation":[{"name":"Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK"},{"name":"Southampton NIHR Respiratory Biomedical Research Unit, University Hospital Southampton, Southampton SO16 6YD, UK"},{"name":"Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2016,8,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1111\/cea.12309","article-title":"Epithelial function and dysfunction in asthma","volume":"44","author":"Loxham","year":"2014","journal-title":"Clin. Exp. Allergy"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1183\/09031936.00141514","article-title":"The innate immune function of airway epithelial cells in inflammatory lung disease","volume":"45","author":"Hiemstra","year":"2015","journal-title":"Eur. Respir. J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"L1047","DOI":"10.1152\/ajplung.00279.2015","article-title":"Homeostasis and its disruption in the lung microbiome","volume":"309","author":"Dickson","year":"2015","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1128\/MMBR.00028-09","article-title":"Working toward the future: Insights into Francisella tularensis pathogenesis and vaccine development","volume":"73","author":"Pechous","year":"2009","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1097\/00000441-196108000-00004","article-title":"Studies with tularemia vaccines in volunteers. IV. Brucella aggiutinins in vaccinated and nonvaccinated volunteers challenged with Pasteurella tularensis","volume":"242","author":"Saslaw","year":"1961","journal-title":"Am. J. Med. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/S0733-8627(02)00005-6","article-title":"Threats in bioterrorism. I: CDC category A agents","volume":"20","author":"Darling","year":"2002","journal-title":"Emerg. Med. Clin. N. Am."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1128\/br.26.3.354-373.1962","article-title":"Soviet viable Pasteurella tularensis vaccines. A review of selected articles","volume":"26","author":"Tigertt","year":"1962","journal-title":"Bacteriol. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1093\/bmb\/ldr007","article-title":"Melioidosis: A clinical overview","volume":"99","author":"Limmathurotsakul","year":"2011","journal-title":"Br. Med. Bull."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Van Zandt, K.E., Greer, M.T., and Gelhaus, H.C. (2013). Glanders: An overview of infection in humans. Orphanet J. Rare Dis.","DOI":"10.1186\/1750-1172-8-131"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1128\/JCM.43.2.970-972.2005","article-title":"Cutaneous melioidosis in a man who was taken as a prisoner of war by the Japanese during World War II","volume":"43","author":"Ngauy","year":"2005","journal-title":"J. Clin. Microbiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1099\/00207713-48-1-317","article-title":"Burkholderia thailandensis sp. nov., a Burkholderia pseudomallei-like species","volume":"48","author":"Brett","year":"1998","journal-title":"Int. J. Syst. Bacteriol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5402","DOI":"10.1128\/IAI.00626-08","article-title":"Burkholderia thailandensis as a model system for the study of the virulence-associated type III secretion system of Burkholderia pseudomallei","volume":"76","author":"Haraga","year":"2008","journal-title":"Infect. Immun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1016\/j.ejpb.2012.12.014","article-title":"In vitro and ex vivo models of human asthma","volume":"84","author":"Blume","year":"2013","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1016\/j.jaci.2013.03.005","article-title":"TNF-alpha-mediated bronchial barrier disruption and regulation by src-family kinase activation","volume":"132","author":"Hardyman","year":"2013","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/j.intimp.2011.12.006","article-title":"Glucocorticoids enhance airway epithelial barrier integrity","volume":"12","author":"Sekiyama","year":"2012","journal-title":"Int. Immunopharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Heijink, I.H., Jonker, M.R., de Vries, M., van Oosterhout, A.J., Telenga, E., ten Hacken, N.H., Postma, D.S., and van den Berge, M. (2016). Budesonide and fluticasone propionate differentially affect the airway epithelial barrier. Respir. Res.","DOI":"10.1186\/s12931-015-0318-z"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"David, J., Bell, R.E., and Clark, G.C. (2015). Mechanisms of disease: Host-pathogen interactions between burkholderia species and lung epithelial cells. Front. Cell. Infect. Microbiol.","DOI":"10.3389\/fcimb.2015.00080"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1165\/rcmb.2003-0329OC","article-title":"Toll-like receptors in normal and cystic fibrosis airway epithelial cells","volume":"30","author":"Muir","year":"2004","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1165\/rcmb.2003-0388OC","article-title":"Activation of airway epithelial cells by toll-like receptor agonists","volume":"31","author":"Sha","year":"2004","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"28700","DOI":"10.1074\/jbc.M703576200","article-title":"Role of p38 MAP kinase and transforming growth factor-beta signaling in transepithelial migration of invasive bacterial pathogens","volume":"282","author":"Beisswenger","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1111\/j.1574-695X.2008.00453.x","article-title":"TLR 5, but neither TLR2 nor TLR4, is involved in lung epithelial cell response to Burkholderia cenocepacia","volume":"54","author":"Balloy","year":"2008","journal-title":"FEMS Immunol. Med. Microbiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2814","DOI":"10.1128\/JB.01567-07","article-title":"The type III toxins of Pseudomonas aeruginosa disrupt epithelial barrier function","volume":"190","author":"Soong","year":"2008","journal-title":"J. Bacteriol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1165\/rcmb.2014-0082OC","article-title":"Staphylococcus aureus hemolysin A disrupts cell-matrix adhesions in human airway epithelial cells","volume":"52","author":"Hermann","year":"2015","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"35891","DOI":"10.1074\/jbc.M111.295386","article-title":"Staphylococcus aureus protein A mediates invasion across airway epithelial cells through activation of RhoA GTPase signaling and proteolytic activity","volume":"286","author":"Soong","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3134","DOI":"10.1128\/IAI.01772-05","article-title":"Rhamnolipids are virulence factors that promote early infiltration of primary human airway epithelia by Pseudomonas aeruginosa","volume":"74","author":"Zulianello","year":"2006","journal-title":"Infect. Immun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"G1029","DOI":"10.1152\/ajpgi.00003.2012","article-title":"Mechanism of protection of transepithelial barrier function by Lactobacillus salivarius: Strain dependence and attenuation by bacteriocin production","volume":"303","author":"Miyauchi","year":"2012","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.1183\/09031936.96.09091913","article-title":"Bacterial-induced release of inflammatory mediators by bronchial epithelial cells","volume":"9","author":"Khair","year":"1996","journal-title":"Eur. Respir. J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1016\/j.jaci.2007.10.041","article-title":"Glucocorticoid actions on airway epithelial responses in immunity: Functional outcomes and molecular targets","volume":"120","author":"Stellato","year":"2007","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"L11","DOI":"10.1152\/ajplung.00488.2005","article-title":"Downregulation by a long-acting beta2-adrenergic receptor agonist and corticosteroid of Staphylococcus aureus-induced airway epithelial inflammatory mediator production","volume":"291","author":"Fragaki","year":"2006","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.jaci.2011.05.038","article-title":"Defective epithelial barrier function in asthma","volume":"128","author":"Xiao","year":"2011","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1016\/0035-9203(95)90078-0","article-title":"Quantitative recovery of Burkholderia pseudomallei from soil in Thailand","volume":"89","author":"Smith","year":"1995","journal-title":"Trans. R. Soc. Trop. Med. Hyg."}],"container-title":["Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-0817\/5\/3\/53\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T19:27:41Z","timestamp":1760210861000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-0817\/5\/3\/53"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,8,3]]},"references-count":31,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2016,9]]}},"alternative-id":["pathogens5030053"],"URL":"https:\/\/doi.org\/10.3390\/pathogens5030053","relation":{},"ISSN":["2076-0817"],"issn-type":[{"value":"2076-0817","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,8,3]]}}}