Protein Fights Off Urinary Tract Infections

STOCKHOLM, June 5 – A protein produced by urinary tract epithelial cells, which appears within minutes of the onset of a urinary tract infection, seems to have potent antimicrobial effects.

Despite its proximity to the environment, the human urinary tract usually remains sterile - mainly, it has been thought, because the regular flow of urine prevents bacteria from attaching to the tissue.

Now Swedish researchers report they have found another way the body prevents disease - the antimicrobial protein that is produced by epithelial cells in the urinary tract within minutes of the beginning of an infection.

The finding could point the way to new ways to prevent urinary tract infections, which are among the 10 most common reasons for outpatient visits, according to Annelie Brauner, M.D., Ph.D., of the Karolinska Institute here. As many as six in 10 women will develop at least one urinary tract infection during their lifetime and 20 % will have recurrent infections.

"Antibiotic-resistant bacteria are a growing problem," Dr. Brauner said. "As the development of resistance to the body's own antibiotic is very rare, it can be used as an alternative or a complement to conventional antibiotic medication."

The protein, dubbed LL-37, is part of a family of peptides known as cathelicidins, which are expressed in circulating neutrophils and myeloid bone marrow cells, in epithelial cells of the skin and gastrointestinal, and in the epididymis and lungs, Dr. Brauner and colleagues noted in the June 4 online issue of Nature Medicine.

Suspecting that cathelicidin might play a role in preventing urinary tract infections, Dr. Brauner and colleagues tested the urine of 28 healthy children and 29 with either pyelonephritis or cystitis. All had the protein in their urine but the sick children had higher levels: the median for the healthy children was 0.3 nanograms per milliliter, compared with 2.4. The difference was statistically significant at P<0.001.

In in vitro experiments, the researchers found that cathelicidin is found in epithelial cells; if the cells are then infected with uropathogenic E. coli, LL-37 and its precursor protein, pro-LL-37, are released into the cell medium five minutes after the bacterial exposure.

"We were able to show that LL-37 is produced in the epithelial cells of the urinary tracts and the kidneys, and that its build-up and secretion occur within a few minutes after a bacterial attack," Dr. Brauner said.

During infection, epithelial cells rapidly increase production of cathelicidin peptide to protect the urinary tract from bacterial invasion, and the "second wave" of cathelicidin comes with invading leukocytes which are recruited by the initial secretion.

In mice genetically engineered to be without the murine equivalent of the cathelicidin gene, the number of bacteria that attached to urinary bladders an hour after exposure to E. coli was significantly higher than in control mice, as was the infection rate 48 hours after the challenge. Both differences were significant at P<0.05.

Finally, the researchers showed that strains of E. coli known to cause invasive infections of the upper urinary tract, pyelonephritis, were more resistant to synthetic LL-37 than strains isolated from children with infection of the lower urinary tract, or cystitis. The difference was significant at P<0.05.

The significance of the finding may lie in better ways to treat recurrent infections, Dr. Brauner said.

"Our findings point to a new way to prevent the development of urinary tract infection by boosting the antibacterial peptide LL-37," she said. "For patients suffering from recurrent urinary tract infection, attack would quite simply be the best form of defense."