The spingosine-1-phosphate analogue FTY720 impairs mucosal immunity and clearance of the enteric pathogen Citrobacter rodentium

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dc.contributor.authorMurphy, Carola T.
dc.contributor.authorHall, Lindsay J.
dc.contributor.authorHurley, Grainne
dc.contributor.authorQuinlan, Aoife
dc.contributor.authorMacSharry, John
dc.contributor.authorShanahan, Fergus
dc.contributor.authorNally, Kenneth
dc.contributor.authorMelgar, Silvia
dc.contributor.funderScience Foundation Irelanden
dc.date.accessioned2012-07-23T14:24:49Z
dc.date.available2012-07-23T14:24:49Z
dc.date.issued2012-08
dc.date.updated2012-07-19T13:57:53Z
dc.description.abstractThe sphingosine-1-phosphate (S1P) analogue, FTY720, is therapeutically efficacious in multiple sclerosis and in the prevention of transplant rejection. It prevents migration of lymphocytes to sites of pathology by trapping them within the peripheral lymph nodes, the mesenteric lymph nodes (MLNs) and Peyer's patches. However, evidence suggests that its clinical use may increase the risk of mucosal infections. We investigated the impact of FTY720 treatment on susceptibility to gastrointestinal infection with the mouse enteric pathogen, Citrobacter rodentium (C. rodentium). This attaching and effacing bacterium induces a transient bacterial colitis in immunocompetent mice, which resembles human infection with pathogenic Escherichia coli. FTY720 treatment induced peripheral blood lymphopenia, trapped lymphocytes in the MLNs and prevented clearance of bacteria when mice were infected with luciferase-tagged C. rodentium. FTY720-treated C. rodentium-infected mice had enhanced colonic inflammation, with significantly higher colon mass, colonhistopathology and neutrophil infiltration, when compared with vehicle-infected animals. In addition, FTY720-treated infected mice had significantly lower numbers of colonic dendritic cells, macrophages and T cells. Gene expression analysis demonstrated that FTY720-treated infected mice had an impaired innate immuneresponse and a blunted mucosal adaptive immune response including Th1 cytokines. The data demonstrate that the S1P analogue, FTY720, adversely affects the immune response and clearance of C. rodentium.en
dc.description.sponsorshipScience Foundation Ireland (02/CE/B124); Science Foundation Ireland (07/CE/B1368)en
dc.description.statusPeer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationCarola T. Murphy, Lindsay J. Hall, Grainne Hurley, Aoife Quinlan, John MacSharry, Fergus Shanahan, Kenneth Nally, Silvia Melgar (2012) 'The Spingosine-1-Phosphate Analogue FTY720 Impairs Mucosal Immunity and Clearance of the Enteric Pathogen Citrobacter rodentium'. Infection and Immunity, 80 (8):2712-2723. doi: 10.1128/​IAI.06319-11en
dc.identifier.doi10.1128/​IAI.06319-11
dc.identifier.endpage2723en
dc.identifier.issn0019-9567
dc.identifier.issn1098-5522
dc.identifier.issued8en
dc.identifier.journaltitleInfection and Immunityen
dc.identifier.startpage2712en
dc.identifier.urihttps://hdl.handle.net/10468/639
dc.identifier.volume80en
dc.language.isoenen
dc.publisherAmerican Society for Microbiologyen
dc.relation.urihttp://iai.asm.org/content/80/8/2712.abstract
dc.rightsCopyright © 2012, American Society for Microbiology. All Rights Reserved.en
dc.subjectS1Pen
dc.subjectInfectionen
dc.subjectImmunityen
dc.subjectMultiple sclerosisen
dc.titleThe spingosine-1-phosphate analogue FTY720 impairs mucosal immunity and clearance of the enteric pathogen Citrobacter rodentiumen
dc.typeArticle (peer-reviewed)en
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