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Abstract
Uropathogenic E. coli (UPEC) expressing type 1 pili underlie most urinary tract infections
(UTIs). UPEC adherence to the bladder urothelium induces a rapid apoptosis and exfoliation
of terminally differentiated urothelial cells, a critical event in pathogenesis. Of
the four major uroplakin proteins that are densely expressed on superficial urothelial
cells, UPIa serves as the receptor for type 1-piliated UPEC, but the contributions
of uroplakins to cell death are not known. We examined the role of differentiation
and uroplakin expression on UPEC-induced cell death. Utilizing in vitro models of
urothelial differentiation, we demonstrated induction of tissue-specific differentiation
markers including uroplakins. UPEC-induced urothelial cell death was shown to increase
with enhanced differentiation but required expression of uroplakin III: infection
with an adenovirus encoding uroplakin III significantly increased cell death, while
siRNA directed against uroplakin III abolished UPEC-induced cell death. In a murine
model of UTI where superficial urothelial cells were selectively eroded to expose
less differentiated cells, urothelial apoptosis was reduced, indicating a requirement
for differentiation in UPEC-induced apoptosis in vivo. These data suggest that induction
of uroplakin III during urothelial differentiation sensitizes cells to UPEC-induced
death. Thus, uroplakin III plays a pivotal role in UTI pathogenesis.