Role of TLR4 in Escherichia coli urinary tract infection

Research output: ThesisDoctoral Thesis (compilation)

Abstract

In this thesis we have used P fimbriated E. coli as a model to investigate the mechanisms of bacterial recognition and cell activation by the urinary tract (UT) epithelium. We show that Toll like receptor 4 (TLR4) is crucial for the recognition and host response to P fimbriated E. coli. This response was independent of LPS and did not require CD14. TLR4 was abundant on epithelial cells throughout the human urinary tract, while CD14 was absent from this compartment, as shown by immunohistochemistry on mucosal biopsies. In vitro infection of the biopsies with uropathogenic E. coli triggered a cytokine response. This response was absent when using avirulent control strains, showing that the human urinary tract epithelium is able to discriminate non-virulent strains from pathogens.

We propose a mechanism for the discrete recognition of P fimbriated E. coli in which the glycosphingolipid (GSL) receptors for P fimbriae are needed in addition to TLR4, for cell activation. P fimbrial binding to GSLs induces ceramide release from the membrane. This activates TLR4, suggesting that ceramide might act as a signaling intermediate between the GSLs and TLR4.

The TLR4 dependent intracellular signaling pathway in response to P fimbriated E. coli was shown to require the adaptors TRIF/TRAM but not MyD88/TIRAP.

The results show an example of discrete recognition of pathogenic bacteria. They provide a mechanism for how epithelial cells can discriminate avirulent strains from pathogens and control the host response in relation to the type of infecting agent.

Details

Authors
  • Patrik Samuelsson
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Immunology in the medical area
  • Microbiology in the medical area

Keywords

  • mykologi, virologi, mycology, Mikrobiologi, bakteriologi, serologi, transplantation, Microbiology, virology, bacteriology, Immunologi, serology, Immunology, Pathogen, Mucosa, P-fimbriae, Toll like receptor
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
  • [unknown], [unknown], Supervisor, External person
Award date2004 May 19
Publisher
  • Division of Microbiology, Immunology and Glycobiology - MIG, Lund Unviersity
Print ISBNs91-6286044-5
StatePublished - 2004
Publication categoryResearch

Bibliographic note

Defence details Date: 2004-05-19 Time: 10:15 Place: Lecture hall at the dept. of Pathology External reviewer(s) Name: Hultmark, Dan Title: Prof. Affiliation: University of Umeå --- Article: FrendÈus B., C. Wachtler, M. Hedlund, H. Fischer, P. Samuelsson, M. Svensson, and C. Svanborg. Escherishia coli P fimbriae utilize the TLR4 receptor pathway for cell activation. Mol.Microbiol. 2001, 40:37-51. Article: Samuelsson P., L. Hang, B. Wullt, H. Irjala and C. Svanborg. Toll like Receptor 4 Expression and Cytokine Responses in the Human Urinary Tract Mucosa. Infect. Immun. 2004, 72 (6).Samuelsson P., N. Roche, E. Gustafsson, H. Fischer, G. Godaly, M. Hedlund, J. Laurson, M-L Svensson, C. Svanborg. Glycosphingolipids as ligand recognition receptors in Toll-like receptor 4 dependent cell activation: Ceramide as a potential signaling intermediate. Manuscript Article: Fischer H., P. Samuelsson, M. Yamamoto, K Hoebe, C. Tallqvist, S. Akira, B. Beutler, C. Svanborg. Pathogen recognition by Toll like receptors: pathogens and commensals use different signal transduction pathways. Submitted