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

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Date
2012-08
Authors
Murphy, Carola T.
Hall, Lindsay J.
Hurley, Grainne
Quinlan, Aoife
MacSharry, John
Shanahan, Fergus
Nally, Kenneth
Melgar, Silvia
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American Society for Microbiology
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Abstract
The 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.
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S1P , Infection , Immunity , Multiple sclerosis
Citation
Carola 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.06319-11
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Copyright © 2012, American Society for Microbiology. All Rights Reserved.