Mechanism of pathogen-specific TLR4 activation in the mucosa: fimbriae, recognition receptors and adaptor protein selection.
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-beta (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 may be engaged specifically by pathogens, when the proper cell surface receptors are engaged by virulence ligands.
Fischer
Hans
H
Department of Microbiology, Immunology and Glycobiology, Institute of Laboratory Medicine, Lund University, S-22362 Lund, Sweden. Hans.Fischer@mig.lu.se
Yamamoto
Masahiro
M
Akira
Shizuo
S
Beutler
Bruce
B
Svanborg
Catharina
C
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology; D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology; D000818:Animals; D004926:Escherichia coli / Q000276:immunology* / Q000472:pathogenicity; D004927:Escherichia coli Infections / Q000276:immunology* / Q000473:pathology; D010861:Fimbriae, Bacterial / Q000276:immunology*; D018928:Immunity, Mucosal / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*; D014552:Urinary Tract Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D037521:Virulence Factors / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1; D051197:Toll-Like Receptor 4; D037521:Virulence Factors; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse