title: The sphingosine-1-phosphate analogue FTY720 impairs mucosal immunity and clearance of the enteric pathogen Citrobacter rodentium.
abstract: The sphingosine-1-phosphate (S1P) analogue FTY720 is therapeutically efficacious in multiple sclerosis and in the prevention of transplant rejection. It prevents the migration of lymphocytes to sites of pathology by trapping them within the peripheral lymph nodes, 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. This attaching and effacing bacterium induces a transient bacterial colitis in immunocompetent mice that resembles human infection with pathogenic Escherichia coli. FTY720 treatment induced peripheral blood lymphopenia, trapped lymphocytes in the MLNs, and prevented the 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, colon histopathology, and neutrophil infiltration than 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 immune response and a blunted mucosal adaptive immune response, including Th1 cytokines. The data demonstrate that the S1P analogue FTY720 adversely affects the immune response to and clearance of C. rodentium.
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, National University of Ireland, Cork, Ireland.
authors.forename: Carola T
authors.initials: CT
authors.lastname: Murphy
authors.forename: Lindsay J
authors.initials: LJ
authors.lastname: Hall
authors.forename: Grainne
authors.initials: G
authors.lastname: Hurley
authors.forename: Aoife
authors.initials: A
authors.lastname: Quinlan
authors.forename: John
authors.initials: J
authors.lastname: MacSharry
authors.forename: Fergus
authors.initials: F
authors.lastname: Shanahan
authors.forename: Kenneth
authors.initials: K
authors.lastname: Nally
authors.forename: Silvia
authors.initials: S
authors.lastname: Melgar
mesh_terms: D000818:Animals; D044082:Citrobacter rodentium / Q000187:drug effects* / Q000276:immunology; D004756:Enterobacteriaceae Infections / Q000276:immunology / Q000382:microbiology*; D005260:Female; D000068876:Fingolimod Hydrochloride; D005786:Gene Expression Regulation / Q000276:immunology; D018928:Immunity, Mucosal / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008231:Lymphopenia / Q000139:chemically induced; D051379:Mice; D008815:Mice, Inbred Strains; D011409:Propylene Glycols / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D012333:RNA, Messenger; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine