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

Hdl Handle:
http://hdl.handle.net/10147/138403
Title:
A Role for TLR4 in Clostridium difficile Infection and the Recognition of Surface Layer Proteins.
Authors:
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
Affiliation:
Immunomodulation Research Group, School of Biotechnology, Dublin City University, Ireland.
Citation:
A Role for TLR4 in Clostridium difficile Infection and the Recognition of Surface Layer Proteins. 2011, 7 (6):e1002076 PLoS Pathog.
Journal:
PLoS pathogens
Issue Date:
Jun-2011
URI:
http://hdl.handle.net/10147/138403
DOI:
10.1371/journal.ppat.1002076
PubMed ID:
21738466
Abstract:
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.
Language:
en
ISSN:
1553-7374

Full metadata record

DC FieldValue Language
dc.contributor.authorRyan, Anthonyen
dc.contributor.authorLynch, Marken
dc.contributor.authorSmith, Sinead Men
dc.contributor.authorAmu, Sylvieen
dc.contributor.authorNel, Hendrik Jen
dc.contributor.authorMcCoy, Claire Een
dc.contributor.authorDowling, Jennifer Ken
dc.contributor.authorDraper, Eveen
dc.contributor.authorO'Reilly, Vincenten
dc.contributor.authorMcCarthy, Ciaraen
dc.contributor.authorO'Brien, Julieen
dc.contributor.authorNí Eidhin, Déirdreen
dc.contributor.authorO'Connell, Mary Jen
dc.contributor.authorKeogh, Brianen
dc.contributor.authorMorton, Charles Oen
dc.contributor.authorRogers, Thomas Ren
dc.contributor.authorFallon, Padraic Gen
dc.contributor.authorO'Neill, Luke Aen
dc.contributor.authorKelleher, Dermoten
dc.contributor.authorLoscher, Christine Een
dc.date.accessioned2011-07-29T14:17:39Z-
dc.date.available2011-07-29T14:17:39Z-
dc.date.issued2011-06-
dc.identifier.citationA Role for TLR4 in Clostridium difficile Infection and the Recognition of Surface Layer Proteins. 2011, 7 (6):e1002076 PLoS Pathog.en
dc.identifier.issn1553-7374-
dc.identifier.pmid21738466-
dc.identifier.doi10.1371/journal.ppat.1002076-
dc.identifier.urihttp://hdl.handle.net/10147/138403-
dc.description.abstractClostridium 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.-
dc.language.isoenen
dc.titleA Role for TLR4 in Clostridium difficile Infection and the Recognition of Surface Layer Proteins.en
dc.contributor.departmentImmunomodulation Research Group, School of Biotechnology, Dublin City University, Ireland.en
dc.identifier.journalPLoS pathogensen

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