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Mechanisms of Escherichia coli induced transepithelial neutrophil migration

Author

Summary, in English

Mucosal infections trigger an inflammatory response that includes the secretion of cytokines and the recruitment of neutrophils to the infected site. This thesis describes studies examining the molecular mechanisms of neutrophil migration to sites of mucosal bacterial infection.



Escherichia coli (E. coli) infection of epithelial cell layers stimulates chemokine secretion and chemokine receptor expression. Human epithelial cells produced an array of CXC chemokines (e.g., IL-8, GRO, ENA-78, IP-10, MIG) and CC chemokines (e.g., MCP-1, MIP, RANTES) in response to bacterial infection. The chemokine repertoire was shown to be influenced by the fimbrial expression of the infecting strain. Furthermore, E. coli infection increased the expression of chemokine receptors (CXCR1 and CXCR2) on epithelial cells. IL-8 was found to be the major chemoattractant involved in neutrophil migration across infected epithelial cell layers. Transuroepithelial neutrophil migration was also shown to be depending on the level of CXCR1 expression on neutrophils and epithelial cell layers.



The in vitro observations were confirmed in an experimental UTI model. Recombinant P or type 1 fimbriated E. coli stimulated chemokine responses and neutrophil recruitment more efficiently than the non-fimbriated controls. The relevance of IL-8 receptor expression was confirmed in vivo using IL-8 receptor knock-out (mIL-8Rh KO) mice. E. coli infection of mIL-8Rh KO mice caused the neutrophils to leave the blood vessels but they were unable to cross the epithelium and accumulated in the tissues. Bacterial clearance was impaired and tissues were destroyed. Subsequent human studies showed a decrease in CXCR1 expression on neutrophils from patients prone to acute pyelonephritis.



These results provide a first molecular clue to the host defect in patients prone to acute pyelonephritis.

Publishing year

2000

Language

English

Document type

Dissertation

Publisher

Department of Laboratory Medicine, Lund University

Topic

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

Keywords

  • Microbiology
  • UTI
  • mucosa
  • cytokine receptors
  • inflammation
  • neutrophils
  • chemotaxis
  • bacteriology
  • virology
  • mycology
  • Mikrobiologi
  • bakteriologi
  • virologi
  • mykologi

Status

Published

Supervisor

  • [unknown] [unknown]

ISBN/ISSN/Other

  • ISBN: 91-628-4049-5
  • ISNR: LUMEDW/MEMG-0008-SE

Defence date

11 May 2000

Defence time

09:00

Defence place

GK-room (BMC), Sölvegatan 23

Opponent

  • Guy R. Cornelis (Professor)