Uropathogenic E. coli (UPEC) elaborate a variety of surface structures and two-component systems that play critical roles in UTI pathogenesis. The stages of pathogenesis, as determined from animal models and clinical data, include initial bladder colonization and the IBC cycle (A–E), the chronic bladder outcomes of quiescent intracellular reservoir (QIR) formation (F) and chronic cystitis (G), and ureteral ascension and pyelitis/pyelonephritis with increased risk for bacteremia/septicemia. UPEC surface structures that play a role in UTI pathogenesis include lipopolysaccharide (LPS), polysaccharide capsule, flagella, outer membrane vesicles, pili, non-pilus adhesins, outer membrane proteins (OMPs), toxins, secretion systems, and TonB-dependent iron uptake receptors, including siderophore receptors. These virulence components are attractive drug and vaccine candidates.

Top panel, Model of P pilus formation by the chaperone-usher pathway in uropathogenic E. coli. After secretion of pilus subunits into the periplasm via the general Sec machinery, periplasmic chaperones (dark green) serve as folding templates, providing a beta-sheet that enables proper folding of the pilin subunits into immunoglobulin-like domains, but in a non-conical orientation, in a mechanism called donor strand complementation. Assembly and anchoring of the pilus occurs at an outer membrane pore known as the usher (orange). The pilus tip adhesin (red) is the first subunit to interact with the usher, via a preferential interaction between the tip adhesin/periplasmic chaperone complex and the usher N-terminal periplasmic domain (NTD, light blue), and this interaction initiates assembly by causing a conformational change in the usher that “unplugs” (Plug, dark blue) the pore and displaces the tip adhesin subunit/chaperone complex to two C-terminal usher domains, CTD1 (yellow) and CTD2 (purple) (, , ). The next pilin subunit/chaperone complex then binds to the NTD and if it has an N-terminal extension that is able to complete the immunoglobulin fold of the preceding subunit in a canonical fashion, this provides the free energy to displace the chaperone, in a process called donor strand exchange, and drive assembly (–, ). In P pili, this occurs repeatedly, incorporating anywhere from hundreds to thousands of PapA major pilin subunits (green) in the pilus, until PapH (brown) is incorporated into pilus. PapH is a terminator because it is unable to undergo donor strand exchange (). Small molecule inhibitors (pink) that disrupt pilus assembly (“pilicides”) or adhesin binding to its receptor (“pilus adhesin antagonists”) have been identified (, ). Bottom panel, Model of sortase-mediated assembly of the endocarditis- and biofilm-associated pilus (Ebp pilus) in E. faecalis (). Unlike CUP pili in Gram-negative bacteria, sortase-assembled pilus subunits are covalently linked. Pilin subunits are first secreted to the outside of the cell via the general Sec machinery, and are retained in the membrane via a hydrophobic domain within their cell wall sorting sequence. Sortase C (SrtC, yellow) cleaves the EbpA (red) LPETG sequence, resulting in an EbpA-SrtC thioacyl intermediate that is resolved by the EbpC (green) Lys186 nucleophile. Pilus polymerization occurs when SrtC processes the EbpC LPSTG sequence at the base of a growing, membrane-associated pilus forming a pilus-SrtC intermediate that is resolved by the Lys186 of an incoming EbpC subunit. EbpB (brown) incorporates at the base of a pilus fiber when its Lys179 nucleophile resolves a pilus-SrtC intermediate. Sortase A (SrtA, blue) processing of the EbpB LPKTN sequence leads to eventual incorporation of the mature pilus into the cell wall. Sortase inhibitors (pink) may be useful for disrupting the virulence potential of Gram-positive uropathogens.