The Cpx stress response system potentiates the fitness and virulence of uropathogenic Escherichia coli.

Strains of uropathogenic Escherichia coli (UPEC) are the primary cause of urinary tract infections, representing one of the most widespread and successful groups of pathogens on the planet. To colonize and persist within the urinary tract, UPEC must be able to sense and respond appropriately to environmental stresses, many of which can compromise the bacterial envelope. The Cpx two-component envelope stress response system is comprised of the inner membrane histidine kinase CpxA, the cytosolic response regulator CpxR, and the periplasmic auxiliary factor CpxP. Here, by using deletion mutants along with mouse and zebrafish infection models, we show that the Cpx system is critical to the fitness and virulence of two reference UPEC strains, the cystitis isolate UTI89 and the urosepsis isolate CFT073. Specifically, deletion of the cpxRA operon impaired the ability of UTI89 to colonize the murine bladder and greatly reduced the virulence of CFT073 during both systemic and localized infections within zebrafish embryos. These defects coincided with diminished host cell invasion by UTI89 and increased sensitivity of both strains to complement-mediated killing and the aminoglycoside antibiotic amikacin. Results obtained with the cpxP deletion mutants were more complicated, indicating variable strain-dependent and niche-specific requirements for this well-conserved auxiliary factor.

Origins and virulence mechanisms of uropathogenic Escherichia coli.

Strains of uropathogenic E. coli (UPEC) are the primary cause of urinary tract infections, including both cystitis and pyelonephritis. These bacteria have evolved a multitude of virulence factors and strategies that facilitate bacterial growth and persistence within the adverse settings of the host urinary tract. Expression of adhesive organelles like type 1 and P pili allow UPEC to bind and invade host cells and tissues within the urinary tract while expression of iron-chelating factors (siderophores) enable UPEC to pilfer host iron stores. Deployment of an array of toxins, including hemolysin and cytotoxic necrotizing factor 1, provide UPEC with the means to inflict extensive tissue damage, facilitating bacterial dissemination as well as releasing host nutrients and disabling immune effector cells. These toxins also have the capacity to modulate, in more subtle ways, host signaling pathways affecting myriad processes, including inflammatory responses, host cell survival, and cytoskeletal dynamics. Here, we discuss the mechanisms by which these and other virulence factors promote UPEC survival and growth within the urinary tract. Comparisons are also made between UPEC and other strains of extraintestinal pathogenic E. coli that, although closely related to UPEC, are distinct in their abilities to colonize the host and cause disease.

Impact of the RNA chaperone Hfq on the fitness and virulence potential of uropathogenic Escherichia coli.

Hfq is a bacterial RNA chaperone involved in the posttranscriptional regulation of many stress-inducible genes via small noncoding RNAs. Here, we show that Hfq is critical for the uropathogenic Escherichia coli (UPEC) isolate UTI89 to effectively colonize the bladder and kidneys in a murine urinary tract infection model system. The disruption of hfq did not affect bacterial adherence to or invasion of host cells but did limit the development of intracellular microcolonies by UTI89 within the terminally differentiated epithelial cells that line the lumen of the bladder. In vitro, the hfq mutant was significantly impaired in its abilities to handle the antibacterial cationic peptide polymyxin B and reactive nitrogen and oxygen radicals and to grow in acidic medium (pH 5.0). Relative to the wild-type strain, the hfq mutant also had a substantially reduced migration rate on motility agar and was less prone to form biofilms. Hfq activities are known to impact the regulation of both the stationary-phase sigma factor RpoS (sigma(S)) and the envelope stress response sigma factor RpoE (sigma(E)). Although we saw similarities among hfq, rpoS, and rpoE deletion mutants in our assays, the rpoE and hfq mutants were phenotypically the most alike. Cumulatively, our data indicate that Hfq likely affects UPEC virulence-related phenotypes primarily by modulating membrane homeostasis and envelope stress response pathways.