Recurrent UTIs may be tied to host immune suppression

"While the dogma within urology was that recurrent UTIs were caused by renewed ascending infection, recent studies in the mouse suggest that recurrent UTIs can also result from establishment of intracellular reservoirs of UPEC within the urothelium," Dr. Klumpp told Urology Times.

"We don't yet understand why the innate response fails to clear all the pathogens and thus enables the establishment of intracellular UPEC reservoirs that may lead to recurrence.

The findings by Dr. Klumpp and colleagues were reported at the AUA annual meeting here.

To test these hypotheses, PhD student Benjamin Billips used a murine cystitis model in which either a prototypical UPEC strain (NU14) or a non-pathogenic enteric E coli strain (MG1655) was inserted into the mouse bladder via catheter. They used quantitative real-time polymerase chain reaction (qRT-PCR) or enzyme-linked immunosorbant assay (ELISA) to evaluate levels of NF-kB-regulated inflammatory cytokines in the bladder and urine 4 hours after infection.

They found that the UPEC suppressed secretion of the cytokines interleukin-8 (IL-8), IL-6, and the mouse chemokines KC and Mip2 when compared with the nonpathogenic fecal strain of bacteria. In addition, the UPEC recruited fewer neutrophils to the lumen. NF-kB suppression by the UPEC also potentiated type-I pili-induced apoptosis in urothelial cells.

The researchers are currently investigating the molecular mechanisms of immune evasion by UPEC. Billips is currently screening a pool of 6,000 NU14 mutant organisms for their ability to induce elevated IL-8 secretion in human urothelial cells. The goal of this screen is to identify mutant strains with attenuated capacity for chemokine suppression.

"By identifying the genes that are altered in these mutants, we will identify the bacterial factors that actively alter the host response and [will] likely determine how these factors contribute to UPEC virulence," Dr. Klumpp told Urology Times.

Thus far, he and his colleagues have identified three mutant strains of NU14 that induce at least two-fold greater IL-8 levels than wild-type NU14. Two of these mutants were less virulent than even the nonpathogenic enteric strain, MG1655, as measured by decreased ability to colonize bladder cell cultures.

"By determining the virulence factors that UPEC employ to modulate the host inflammatory response, we may identify drug targets which impede urothelial vulnerabilities to pathogens," Dr. Klumpp said. "Understanding the mechanisms by which UPEC suppresses the host response may lead to future therapies that prevent recurrence of urinary tract infections."