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A Role for TLR4 in Clostridium difficile Infection and the Recognition of Surface Layer Proteins

Clostridium difficile is the etiological agent of antibiotic-associated diarrhoea (AAD) and pseudomembranous colitis in humans. The role of the surface layer proteins (SLPs) in this disease has not yet been fully explored. The aim of this study was to investigate a role for SLPs in the recognition o...

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Autores principales: Ryan, Anthony, Lynch, Mark, Smith, Sinead M., Amu, Sylvie, Nel, Hendrik J., McCoy, Claire E., Dowling, Jennifer K., Draper, Eve, O'Reilly, Vincent, McCarthy, Ciara, O'Brien, Julie, Ní Eidhin, Déirdre, O'Connell, Mary J., Keogh, Brian, Morton, Charles O., Rogers, Thomas R., Fallon, Padraic G., O'Neill, Luke A., Kelleher, Dermot, Loscher, Christine E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3128122/
https://www.ncbi.nlm.nih.gov/pubmed/21738466
http://dx.doi.org/10.1371/journal.ppat.1002076
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author Ryan, Anthony
Lynch, Mark
Smith, Sinead M.
Amu, Sylvie
Nel, Hendrik J.
McCoy, Claire E.
Dowling, Jennifer K.
Draper, Eve
O'Reilly, Vincent
McCarthy, Ciara
O'Brien, Julie
Ní Eidhin, Déirdre
O'Connell, Mary J.
Keogh, Brian
Morton, Charles O.
Rogers, Thomas R.
Fallon, Padraic G.
O'Neill, Luke A.
Kelleher, Dermot
Loscher, Christine E.
author_facet Ryan, Anthony
Lynch, Mark
Smith, Sinead M.
Amu, Sylvie
Nel, Hendrik J.
McCoy, Claire E.
Dowling, Jennifer K.
Draper, Eve
O'Reilly, Vincent
McCarthy, Ciara
O'Brien, Julie
Ní Eidhin, Déirdre
O'Connell, Mary J.
Keogh, Brian
Morton, Charles O.
Rogers, Thomas R.
Fallon, Padraic G.
O'Neill, Luke A.
Kelleher, Dermot
Loscher, Christine E.
author_sort Ryan, Anthony
collection PubMed
description Clostridium difficile is the etiological agent of antibiotic-associated diarrhoea (AAD) and pseudomembranous colitis in humans. The role of the surface layer proteins (SLPs) in this disease has not yet been fully explored. The aim of this study was to investigate a role for SLPs in the recognition of C. difficile and the subsequent activation of the immune system. Bone marrow derived dendritic cells (DCs) exposed to SLPs were assessed for production of inflammatory cytokines, expression of cell surface markers and their ability to generate T helper (Th) cell responses. DCs isolated from C3H/HeN and C3H/HeJ mice were used in order to examine whether SLPs are recognised by TLR4. The role of TLR4 in infection was examined in TLR4-deficient mice. SLPs induced maturation of DCs characterised by production of IL-12, TNFα and IL-10 and expression of MHC class II, CD40, CD80 and CD86. Furthermore, SLP-activated DCs generated Th cells producing IFNγ and IL-17. SLPs were unable to activate DCs isolated from TLR4-mutant C3H/HeJ mice and failed to induce a subsequent Th cell response. TLR4(−/−) and Myd88(−/−), but not TRIF(−/−) mice were more susceptible than wild-type mice to C. difficile infection. Furthermore, SLPs activated NFκB, but not IRF3, downstream of TLR4. Our results indicate that SLPs isolated from C. difficile can activate innate and adaptive immunity and that these effects are mediated by TLR4, with TLR4 having a functional role in experimental C. difficile infection. This suggests an important role for SLPs in the recognition of C. difficile by the immune system.
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spelling pubmed-31281222011-07-07 A Role for TLR4 in Clostridium difficile Infection and the Recognition of Surface Layer Proteins Ryan, Anthony Lynch, Mark Smith, Sinead M. Amu, Sylvie Nel, Hendrik J. McCoy, Claire E. Dowling, Jennifer K. Draper, Eve O'Reilly, Vincent McCarthy, Ciara O'Brien, Julie Ní Eidhin, Déirdre O'Connell, Mary J. Keogh, Brian Morton, Charles O. Rogers, Thomas R. Fallon, Padraic G. O'Neill, Luke A. Kelleher, Dermot Loscher, Christine E. PLoS Pathog Research Article Clostridium difficile is the etiological agent of antibiotic-associated diarrhoea (AAD) and pseudomembranous colitis in humans. The role of the surface layer proteins (SLPs) in this disease has not yet been fully explored. The aim of this study was to investigate a role for SLPs in the recognition of C. difficile and the subsequent activation of the immune system. Bone marrow derived dendritic cells (DCs) exposed to SLPs were assessed for production of inflammatory cytokines, expression of cell surface markers and their ability to generate T helper (Th) cell responses. DCs isolated from C3H/HeN and C3H/HeJ mice were used in order to examine whether SLPs are recognised by TLR4. The role of TLR4 in infection was examined in TLR4-deficient mice. SLPs induced maturation of DCs characterised by production of IL-12, TNFα and IL-10 and expression of MHC class II, CD40, CD80 and CD86. Furthermore, SLP-activated DCs generated Th cells producing IFNγ and IL-17. SLPs were unable to activate DCs isolated from TLR4-mutant C3H/HeJ mice and failed to induce a subsequent Th cell response. TLR4(−/−) and Myd88(−/−), but not TRIF(−/−) mice were more susceptible than wild-type mice to C. difficile infection. Furthermore, SLPs activated NFκB, but not IRF3, downstream of TLR4. Our results indicate that SLPs isolated from C. difficile can activate innate and adaptive immunity and that these effects are mediated by TLR4, with TLR4 having a functional role in experimental C. difficile infection. This suggests an important role for SLPs in the recognition of C. difficile by the immune system. Public Library of Science 2011-06-30 /pmc/articles/PMC3128122/ /pubmed/21738466 http://dx.doi.org/10.1371/journal.ppat.1002076 Text en Ryan et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Ryan, Anthony
Lynch, Mark
Smith, Sinead M.
Amu, Sylvie
Nel, Hendrik J.
McCoy, Claire E.
Dowling, Jennifer K.
Draper, Eve
O'Reilly, Vincent
McCarthy, Ciara
O'Brien, Julie
Ní Eidhin, Déirdre
O'Connell, Mary J.
Keogh, Brian
Morton, Charles O.
Rogers, Thomas R.
Fallon, Padraic G.
O'Neill, Luke A.
Kelleher, Dermot
Loscher, Christine E.
A Role for TLR4 in Clostridium difficile Infection and the Recognition of Surface Layer Proteins
title A Role for TLR4 in Clostridium difficile Infection and the Recognition of Surface Layer Proteins
title_full A Role for TLR4 in Clostridium difficile Infection and the Recognition of Surface Layer Proteins
title_fullStr A Role for TLR4 in Clostridium difficile Infection and the Recognition of Surface Layer Proteins
title_full_unstemmed A Role for TLR4 in Clostridium difficile Infection and the Recognition of Surface Layer Proteins
title_short A Role for TLR4 in Clostridium difficile Infection and the Recognition of Surface Layer Proteins
title_sort role for tlr4 in clostridium difficile infection and the recognition of surface layer proteins
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3128122/
https://www.ncbi.nlm.nih.gov/pubmed/21738466
http://dx.doi.org/10.1371/journal.ppat.1002076
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