title: Modulation of Human Airway Barrier Functions during Burkholderia thailandensis and Francisella tularensis Infection Running Title: Airway Barrier Functions during Bacterial Infections.
abstract: 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 24-72 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-α release. An increase in ionic permeability and TNF-α 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-α release. TNF blocking antibody Enbrel(®) 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.
authors.affiliation: Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK. c.blume@soton.ac.uk.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Blume
authors.affiliation: Defence Science and Technology Laboratory (Dstl), Porton Down, Salisbury SP4 0JQ, UK. JDAVID@mail.dstl.gov.uk.
authors.forename: Jonathan
authors.initials: J
authors.lastname: David
authors.affiliation: Defence Science and Technology Laboratory (Dstl), Porton Down, Salisbury SP4 0JQ, UK. rachel.e.bell@kcl.ac.uk.|Centre for Molecular and Cellular Biology of Inflammation, Guy's Campus, King's College London, London SE1 1UL, UK. rachel.e.bell@kcl.ac.uk.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Bell
authors.affiliation: Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK. J.R.Laver@soton.ac.uk.
authors.forename: Jay R
authors.initials: JR
authors.lastname: Laver
authors.affiliation: Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK. R.C.Read@soton.ac.uk.|Southampton NIHR Respiratory Biomedical Research Unit, University Hospital Southampton, Southampton SO16 6YD, UK. R.C.Read@soton.ac.uk.|Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, UK. R.C.Read@soton.ac.uk.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Read
authors.affiliation: Defence Science and Technology Laboratory (Dstl), Porton Down, Salisbury SP4 0JQ, UK. GCCLARK@dstl.gov.uk.
authors.forename: Graeme C
authors.initials: GC
authors.lastname: Clark
authors.affiliation: Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK. D.E.Davies@soton.ac.uk.|Southampton NIHR Respiratory Biomedical Research Unit, University Hospital Southampton, Southampton SO16 6YD, UK. D.E.Davies@soton.ac.uk.|Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, UK. D.E.Davies@soton.ac.uk.
authors.forename: Donna E
authors.initials: DE
authors.lastname: Davies
authors.affiliation: Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK. E.J.Swindle@soton.ac.uk.|Southampton NIHR Respiratory Biomedical Research Unit, University Hospital Southampton, Southampton SO16 6YD, UK. E.J.Swindle@soton.ac.uk.|Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, UK. E.J.Swindle@soton.ac.uk.
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Swindle
keywords: Burkholderia thailandensis; Fransicella tularensis; airway epithelium; bacterial infection; bacterial passage; barrier functions; fluticasone propionate