Mechanism of pathogen-specific TLR4 activation in the mucosa: Fimbriae, recognition receptors and adaptor protein selection

Hans Fischer, Masahiro Yamamoto, Shizuo Akira, Bruce Beutler, Catharina Svanborg

Research output: Contribution to journalArticle

110 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)267-277
Number of pages11
JournalEuropean Journal of Immunology
Volume36
Issue number2
DOIs
StatePublished - Feb 1 2006

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Keywords

  • Adaptor proteins
  • Innate immunity
  • Mucosa
  • Pathogen recognition
  • TLR4

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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