TY - JOUR
T1 - Mechanism of pathogen-specific TLR4 activation in the mucosa
T2 - Fimbriae, recognition receptors and adaptor protein selection
AU - Fischer, Hans
AU - Yamamoto, Masahiro
AU - Akira, Shizuo
AU - Beutler, Bruce
AU - Svanborg, Catharina
PY - 2006/2
Y1 - 2006/2
N2 - The mucosal host defence discriminates pathogens from commensals, and prevents infection while allowing the normal flora to persist. Paradoxically, Toll-like receptors (TLR) control the mucosal defence against pathogens, even though the TLR recognise conserved molecules like LPS, which are shared between pathogens and commensals. This study proposes a mechanism of pathogen-specific mucosal TLR4 activation, involving adhesive ligands and their host cell receptors. TLR4 signalling was activated in CD14-negative, LPS-unresponsive epithelial cells by P fimbriated, uropathogenic Escherichia coli but not by a mutant lacking fimbriae. Epithelial TLR4 signalling in vivo involved the glycosphingolipid receptors for P fimbriae and the adaptor proteins Toll/IL-1R (TIR) domain-containing adaptor inducing IFN-β (TRIF)/TRIF-related adaptor molecule (TRAM), but myeloid differentiation protein 88 (MyD88)/TIR domain-containing adaptor protein were not required for the epithelial response. Substituting the P fimbriae with type 1 fimbriae changed TLR4 signalling from the TRIF to the MyD88 adaptor pathway. In addition, the adaptor proteins and the fimbrial type were found to influence bacterial clearance. Trif-/- and Tram-/- mice remained infected with P fimbriated E. coli but cleared the type 1 fimbriated strain, while Myd88-/- mice became carriers of both the P and the type 1 fimbriated bacteria. Thus, TLR4 maybe engaged specifically by pathogens, when the proper cell surface receptors are engaged by virulence ligands.
AB - The mucosal host defence discriminates pathogens from commensals, and prevents infection while allowing the normal flora to persist. Paradoxically, Toll-like receptors (TLR) control the mucosal defence against pathogens, even though the TLR recognise conserved molecules like LPS, which are shared between pathogens and commensals. This study proposes a mechanism of pathogen-specific mucosal TLR4 activation, involving adhesive ligands and their host cell receptors. TLR4 signalling was activated in CD14-negative, LPS-unresponsive epithelial cells by P fimbriated, uropathogenic Escherichia coli but not by a mutant lacking fimbriae. Epithelial TLR4 signalling in vivo involved the glycosphingolipid receptors for P fimbriae and the adaptor proteins Toll/IL-1R (TIR) domain-containing adaptor inducing IFN-β (TRIF)/TRIF-related adaptor molecule (TRAM), but myeloid differentiation protein 88 (MyD88)/TIR domain-containing adaptor protein were not required for the epithelial response. Substituting the P fimbriae with type 1 fimbriae changed TLR4 signalling from the TRIF to the MyD88 adaptor pathway. In addition, the adaptor proteins and the fimbrial type were found to influence bacterial clearance. Trif-/- and Tram-/- mice remained infected with P fimbriated E. coli but cleared the type 1 fimbriated strain, while Myd88-/- mice became carriers of both the P and the type 1 fimbriated bacteria. Thus, TLR4 maybe engaged specifically by pathogens, when the proper cell surface receptors are engaged by virulence ligands.
KW - Adaptor proteins
KW - Innate immunity
KW - Mucosa
KW - Pathogen recognition
KW - TLR4
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U2 - 10.1002/eji.200535149
DO - 10.1002/eji.200535149
M3 - Article
C2 - 16385628
AN - SCOPUS:32944465549
SN - 0014-2980
VL - 36
SP - 267
EP - 277
JO - European Journal of Immunology
JF - European Journal of Immunology
IS - 2
ER -