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

108 Citations (Scopus)

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 2006

Fingerprint

Mucous Membrane
Toll-Like Receptors
Proteins
Fimbriae Proteins
Uropathogenic Escherichia coli
Ligands
Glycosphingolipids
Cell Surface Receptors
Adhesives
Virulence
Epithelial Cells
Escherichia coli
Bacteria
Infection

Keywords

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

ASJC Scopus subject areas

  • Immunology

Cite this

Mechanism of pathogen-specific TLR4 activation in the mucosa : Fimbriae, recognition receptors and adaptor protein selection. / Fischer, Hans; Yamamoto, Masahiro; Akira, Shizuo; Beutler, Bruce; Svanborg, Catharina.

In: European Journal of Immunology, Vol. 36, No. 2, 02.2006, p. 267-277.

Research output: Contribution to journalArticle

Fischer, Hans ; Yamamoto, Masahiro ; Akira, Shizuo ; Beutler, Bruce ; Svanborg, Catharina. / Mechanism of pathogen-specific TLR4 activation in the mucosa : Fimbriae, recognition receptors and adaptor protein selection. In: European Journal of Immunology. 2006 ; Vol. 36, No. 2. pp. 267-277.
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