Figure 8. Model of UPIIIa mechanisms of UPEC pathogenesis.

(A) UTI pathogenesis in the bladder occurs in distinct kinetic phases. Immediate early host responses include UPIIIa phosphorylation and increased [Ca²⁺]_i (this study), PI3K activation [7], actin rearrangement [50], and increased cAMP [51]. Subsequent early host responses include UPEC internalization [7], NFκB-dependent chemokine production and modulation [12], urothelial apoptotic cascades [11], and bacterial clearance mediated by neutrophils [10]. Late events include adaptive responses that confer protective immunity [40] and establishment of stable UPEC reservoirs within the urothelium [37]. (B) UPEC interaction with uroplakins leads to phosphorylation of the UPIIIa cytoplasmic tail by CK2 and the initiation of two signaling cascades. Elevation in intracellular calcium from intra- and extracellular stores and the associated recruitment of other signaling molecules activates host cell cytoskeletal elements and the endocytosis of UPEC. UPIIIa phosphorylation activates an unknown signaling intermediate that initiates intrinsic and extrinsic apoptotic cascades. Pro-survival signals initiated by TLR activation may shift the balance away from UPIIIa-induced pro-apoptotic signals in those cells where UPEC successfully establish stable intracellular populations.