A role for TLR4 in Clostridium difficile infection and the recognition of surface layer proteins

Anthony Ryan, Mark Lynch, Sinead M. Smith, Sylvie Amu, Hendrik J. Nel, Claire E. McCoy, Jennifer K. Dowling, Eve Draper, Vincent O'Reilly, Ciara McCarthy, Julie O'Brien, Deirdre Ni Eidhin, Mary J. O'Connell, Brian Keogh, Charles O. Morton, Padraic G. Fallon, Luke A. O'Neill, Dermot Kelleher, Christine E. Loscher

    Research output: Contribution to journalArticlepeer-review

    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 ion 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.
    Original languageEnglish
    Article numbere1002076
    Number of pages13
    JournalPLoS Pathogens
    Volume7
    Issue number6
    DOIs
    Publication statusPublished - 2011

    Open Access - Access Right Statement

    Copyright: 2011 Ryan et al. 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 credited.

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