The bladder epithelium is a multilayered structure, consisting of several layers of somewhat undifferentiated basal and intermediate cells underlying a single layer of highly differentiated, often hexagonal, sometimes multinucleated facet cells. The facet cells express a quasi-crystalline array of uroplakin molecules, among which lies the mannosylated receptor recognized by UPEC type 1 pili. The bladder is normally a quiescent structure, turning over its epithelium once every 4-6 months. However, inoculation of UPEC into the bladders of C57BL/6 mice initiates a cascade of host gene transcriptional responses leading to rapid (< 6 hours) exfoliation of the facet cells. Underlying cells begin to differentiate rapidly and the facet cell layer can be reconstituted in 48 hours. This exfoliation may represent a defense mechanism for the host, allowing rapid shedding of a multitude of attached and invaded bacteria, but it also allows the bacteria more ready access to deeper layers of the uroepithelium.
The bladder epithelium utilizes Toll-like receptors (TLR) and the TLR4 co-receptor CD14 to respond to LPS and other molecules presented by E. coli and other bacterial pathogens. Activation of the TLR pathway leads to transcription of pro-inflammatory and anti-apoptotic genes via the action of NF-kappa B. IL-6 has pleiotropic effects and IL-8 is a principal chemoattractant for neutrophils, which are seen infiltrating the bladder in murine and human cystitis. Uropathogenic strains of E. coli, in contrast to laboratory strains, appear to attenuate the production of cytokines in vitro, which may suggest a virulence mechanism at work in the early stages of UTI in vivo.
The importance of type 1 pili in the induction of innate immune responses and the exfoliation response has been examined in a recent manuscript (PDF). We are continuing to utilize microarray technology to examine host responses to various strains of E. coli, and the gene programs active in these bacteria during selected stages of pathogenesis.