Studies of the pathogenesis of Enterohemorrhagic Escherichia coli infections: pathogen virulence factors and host response

Carla Calderon Toledo

Research output: ThesisDoctoral Thesis (compilation)

Abstract

Enterohemorrhagic Escherichia coli (EHEC) is a highly virulent pathogen that can cause diarrhea and a life-threatening disease known as hemolytic uremic syndrome. EHEC possess an array of virulence factors that can exert severe consequences in the host. Shiga toxin constitutes a key virulence factor. Enteropathogenic Escherichia coli (EPEC) is a leading cause of infant diarrhea. EHEC and EPEC are related pathogens that share considerable homology regarding virulence factors. The aim of this study was to describe host-pathogen interactions during EHEC infection using established mouse models. Host detection of infection requires the activation of the innate immune system. Toll-like receptors (TLRs) can detect microbial motifs and initiate a signaling cascade leading to an inflammatory response with the goal to eradicate the pathogen. TLR4 recognizes bacterial lipopolysaccharide and can signal through two pathways that utilize the MyD88 and TRIF adaptor molecules, respectively. In this study MyD88-deficient mice infected with a Shiga toxin-producing E. coli O157:H7 strain developed severe symptoms and an increased bacterial burden, suggesting that the MyD88-dependent pathway is essential for an effective response against EHEC infection and in its absence Shiga toxin-mediated disease is amplified. The adaptive immune response provides long-lasting immunity against subsequent infection. A previous inoculation with EPEC resulted in a protective effect against a subsequent EHEC infection in mice, suggesting a cross-reactive immunity presumably against multiple factors shared by both pathogens. If EHEC bacteria overcome these host immune barriers an intestinal colonization process begins. The expression of intimin and an intact type three secretion system were shown to be necessary for intestinal colonization and virulence in mice. Shiga toxin secreted in the intestinal tract was shown to promote colonization and contribute to intestinal damage and cell death. Subsequently Shiga toxin can translocate the intestinal barrier targeting organs such as the kidney. Shiga toxin was demonstrated in kidneys of mice infected with a Shiga toxin-producing E. coli O157:H7 strain suggesting that the toxin could promote renal damage and severe symptoms.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Paediatrics (Lund)
Supervisors/Advisors
  • Karpman, Diana, Supervisor
Award date2010 Dec 10
Publisher
ISBN (Print)978-91-86671-37-2
Publication statusPublished - 2010

Bibliographical note

Defence details

Date: 2010-12-10
Time: 09:00
Place: Belfragesalen, D15, Biomedicinskt Centrum (BMC)

External reviewer(s)

Name: Karch, Helge
Title: Professor
Affiliation: Universität Münster, Institut für Hygiene, Münster, Germany

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Subject classification (UKÄ)

  • Pediatrics

Keywords

  • host-pathogen
  • MyD88
  • TLRs
  • LEE
  • Shiga toxin
  • HUS
  • EHEC
  • EPEC
  • immune response
  • virulence factors

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