| Escherichia coli is a gram negative, commensal enteric bacterium that under certain conditions can cause a variety of different diseases in humans, including infections of the urinary tract (UTI's). E. coli is the major etiologic agent of all UTI's, including cystitis, and the vast majority of these UTI isolates express a composite, adhesive organelle termed the type 1 pilus or fimbriae that contains the adhesin, FimH at the distal tip. FimH-mediated adherence to receptors on a variety of epithelial cells including bladder epithelial cells has been demonstrated to be a critical initial interaction in the subsequent establishment of a successful infection. Although previously thought to be an extracellular pathogen, we discovered that uropathogenic type 1-piliated E. coli (UPEC) could become internalized in vivo by bladder epithelial cells. We developed an in vitro model using cultured bladder epithelial cells to study the dynamic interactions between uropathogenic E. coli and host cells that may lead to disease. These studies revealed that the adhesin, FimH, was the sole bacterial factor required for invasion. Interactions between FimH and host receptor(s) triggered the activation of Rho family GTPase members (Cdc42 and Rac1), Focal Adhesion Kinase (FAK), PI 3-kinase and actin polymerization ultimately leading to bacterial internalization. Further characterization revealed that Cdc42 activation was one of the first events induced in the invasion pathway, followed by activation of FAK and PI 3-kinase and finally by Rac1 activation. Similar to other invasive pathogens, UPEC exploits pre-existing signaling cascades normally used to maintain actin cytoskeletal integrity to facilitate its internalization into host cells, sequestering itself away from host defenses; however, the mechanism by which UPEC gains entry appears to be unique. These studies have demonstrated that the interactions between UPEC and bladder epithelial cells is more complex than previously thought and may shed insight into the development of more efficacious therapies for the prevention of UTI's. |
