The role of the epithelial cell in Escherichia coli induced neutrophil migration into the urinary tract

Abstract: This study examined the molecular mechanisms of neutrophil migration to sites of mucosal bacterial infection. (1) Bacterial induction of neutrophil chemotactic cytokines and their role in neutrophil migration. Uropathogenic E.coli were shown to stimulate urinary tract epithelial cells to produce a specific array of cytokines including the neutrophil chemoattractant IL-8. IL-8 production was dependent on the adherence properties of the infecting strain. Deliberate colonisation of the human urinary tract with E.coli induced the local production of IL-8 and levels correlated with urinary neutrophil numbers. The E.coli induced IL-8 supported neutrophil migration across urinary tract epithelial layers in vitro and anti-IL-8 antibody blocked this response. The chemotactically active IL-8 was localised to the epithelial surface and these cells contained IL-8 receptor A and B mRNA. (2) The role of epithelial adhesion molecules in E.coli induced transuroepithelial migration. Uroepithelial cells constitutively expressed ICAM-1 and E.coli augmented ICAM-1 expression. Transuroepithelial neutrophil migration was dependent on epithelial ICAM-1 and neutrophil Mac-1 (CD11b/CD18) expression. Thus urinary tract epithelial cells provide two prerequisites for neutrophil migration to the mucosal lumen; neutrophil chemoattractants and cell adhesion molecules. (3) The role of bacterial fimbriae for the induction of inflammation in the urinary tract. Patients and mice infected with a type 1 positive P fimbriated uropathogenic E.coli clone O1:K1:H7 showed significantly higher inflammatory responses than type 1 negative O1:K1:H7 isolates. Insertion of an npt gene into fimH (encoding the type 1 fimbrial adhesin) of a type 1 positive O1:K1:H7 isolate resulted in the loss of the type 1 fimbrial phenotype and a reduction in virulence.