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

Fischer, Hans LU ; Yamamoto, Masahiro; Akira, Shizuo; Beutler, Bruce and Svanborg, Catharina LU (2006) In European Journal of Immunology 36(2). p.267-277
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... (More)
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 maybe engaged specifically by pathogens, when the proper cell surface receptors are engaged by virulence ligands. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
adaptor proteins, innate immunity, pathogen recognition, mucosa, TLR4
in
European Journal of Immunology
volume
36
issue
2
pages
267 - 277
publisher
John Wiley & Sons
external identifiers
  • pmid:16385628
  • wos:000235404500003
  • scopus:32944465549
ISSN
1521-4141
DOI
10.1002/eji.200535149
language
English
LU publication?
yes
id
13762307-22e9-4dff-b9d3-d663be5ddf4e (old id 148412)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16385628&dopt=Abstract
date added to LUP
2007-07-04 09:02:16
date last changed
2019-03-05 02:03:22
@article{13762307-22e9-4dff-b9d3-d663be5ddf4e,
  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-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 maybe engaged specifically by pathogens, when the proper cell surface receptors are engaged by virulence ligands.},
  author       = {Fischer, Hans and Yamamoto, Masahiro and Akira, Shizuo and Beutler, Bruce and Svanborg, Catharina},
  issn         = {1521-4141},
  keyword      = {adaptor proteins,innate immunity,pathogen recognition,mucosa,TLR4},
  language     = {eng},
  number       = {2},
  pages        = {267--277},
  publisher    = {John Wiley & Sons},
  series       = {European Journal of Immunology},
  title        = {Mechanism of pathogen-specific TLR4 activation in the mucosa: Fimbriae, recognition receptors and adaptor protein selection.},
  url          = {http://dx.doi.org/10.1002/eji.200535149},
  volume       = {36},
  year         = {2006},
}