TY - JOUR
T1 - A role for TLR4 in Clostridium difficile infection and the recognition of surface layer proteins
AU - Ryan, Anthony
AU - Lynch, Mark
AU - Smith, Sinead
AU - Amu, Sylvie
AU - Nel, Hendrik
AU - McCoy, Claire
AU - Dowling, Jennifer K.
AU - Draper, Eve
AU - O'Reilly, Vincent
AU - McCarthy, Ciara
AU - O'Brien, Julie
AU - Eidhin, Deirdre
AU - O'Connell, Mary
AU - Keogh, Brian
AU - Morton, Charles
AU - Rogers, Thomas
AU - Fallon, Padraic
AU - O'Neill, Luke
AU - Kelleher, Dermont
AU - Loscher, Christine
PY - 2011
Y1 - 2011
N2 - 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, TNFalpha and IL-10 and expression of MHC class II, CD40, CD80 and CD86. Furthermore, SLP-activated DCs generated Th cells producing IFNgamma 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 NFkappaB, 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.
AB - 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, TNFalpha and IL-10 and expression of MHC class II, CD40, CD80 and CD86. Furthermore, SLP-activated DCs generated Th cells producing IFNgamma 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 NFkappaB, 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.
UR - http://www.ncbi.nlm.nih.gov/pubmed/21738466
U2 - 10.1371/journal.ppat.1002076
DO - 10.1371/journal.ppat.1002076
M3 - Article
VL - 7
JO - PLoS Pathogens
JF - PLoS Pathogens
SN - 1553-7366
IS - 6 (Art. No: e1002076)
M1 - e1002076
ER -