BioWorld International Correspondent

LONDON - A chemical produced by the cells lining the urinary tract helps to prevent urine infections, an international team of researchers found. The chemical, a peptide LL-37, could lead to new drugs for urinary tract infections, and might explain why some people are more susceptible to the infections than others.

Annelie Brauner, professor of clinical microbiology at the Karolinska Institute in Stockholm, Sweden, told BioWorld International, "We think that it may be possible to increase the endogenous production of LL-37 in order to treat or prevent urinary tract infections."

Brauner and her collaborators, from Slovakia, Iceland and the U.S., are preparing to test a drug on a group of women who suffer from recurrent urinary tract infections, to find out if it reduces the number or severity of infections by boosting levels of LL-37. The drug already is available on prescription for other conditions, but Brauner is not willing to provide more details at present.

The team's report on LL-37 is in the June 4, 2006, edition of Nature Medicine in a paper titled "The antimicrobial peptide cathelicidin protects the urinary tract against invasive bacterial infection."

During the past few years, researchers have shown that cells of the immune system, and epithelial cells, produce antimicrobial peptides as part of first-line defense against bacteria at mucosal surfaces. Those antimicrobial peptides have been divided into two groups, the defensins and the cathelicidins.

So far, only one gene encoding a cathelicidin has been found in humans, and its product is LL-37. Brauner and her team set out to examine levels of LL-37 in the urinary tract and investigate its role, if any, in combating urinary tract infections.

They compared LL-37 levels in the urine of children who were healthy with levels in the urine of children with urinary tract infections. They could find LL-37 in both groups, but levels in the sick children were much higher.

Earlier studies had shown that the white blood cells called neutrophils could produce LL-37, but Brauner's group found only a small correlation between levels of the peptide and the number of neutrophils in the children's urine. The source of the LL-37 must be somewhere else, they concluded.

The epithelial cells that line the urinary tract were obvious candidates, because they inevitably come into contact with any invading bacteria. When Brauner and her colleagues cultured human epithelial urinary tract cells, they found that they did indeed produce LL-37 when infected.

"The astonishing thing was," Brauner said, "that they produced the peptide extremely fast, within minutes of infection. This is totally new - normally when a protein is formed, it takes a much longer time. It seems that LL-37 is present in the epithelial cells, ready to be released in the event of bacterial attack."

A further experiment involved infecting the urinary tracts of two groups of mice. The first were wild-type mice; the second lacked the murine equivalent of the human gene for cathelicidin.

The experiment clearly showed that the murine equivalent of LL-37 was biologically important in fighting urinary tract infections: The knockout mice became infected much more easily, became sicker and developed swollen kidneys that were full of bacteria. Both groups lost weight, but the knockout mice lost more. Unlike the wild-type mice, some of the knockout animals died.

"We think this provides solid proof that LL-37 really is a major player in fighting urinary tract infections," Brauner said. "It is our hypothesis that patients who have recurrent urinary tract infections either have lower levels of LL-37, or have LL-37 that works less effectively for some reason."

As well as pursuing a therapy that will boost levels of naturally occurring LL-37, future studies by the group would investigate whether people prone to recurrent urinary tract infections have any mutations or polymorphisms in the gene encoding cathelicidin.

"We also want to find out if LL-37 can be manufactured in a form that can be taken orally, and see if it is possible to increase levels of LL-37 in the urine," Brauner added.

Bacteria also have evolved to take account of the need to circumvent the defenses put up by LL-37. Additional studies reported in Nature Medicine show that strains of Escherichia coli isolated from people with more invasive urinary tract infection (such as pyelonephritis) were significantly less sensitive to synthetic LL-37 than bacteria from people who had infection of the lower urinary tract only.