Homegrown defender: urinary infections face natural guard.

Bacteria are adept at sneaking past our defenses, succeeding most often when swallowed, inhaled, or given free passage via a cut or scratch. But over the past 2 decades, scientists have found that even before the immune system can gin up a response to such intruders, built-in antimicrobial agents in the intestines, lungs, and skin act as a first line of defense. A new study shows that one of these antimicrobial shock troops, a peptide called cathelicidin, patrols another portal as well--the urinary tract.

Cells that line the urinary tract all the way back to the kidneys churn out cathelicidin in response to bacterial invaders, researchers report in the June Nature Medicine. Furthermore, inflammatory cells later deliver a second dose of the antimicrobial peptide to those passages, the scientists say. By damaging the bacterial membrane, cathelicidin usually kills a microbe on contact.

Cells lining the urinary tract normally keep a small supply of cathelicidin on hand, and they crank out more within minutes of contacting bacteria, report Annelie Brauner, a physician and microbiologist at Karolinska

University Hospital in Stockholm, and her colleagues. While urine samples obtained from 28 healthy children contained modest amounts of cathelicidin, samples from 29 children with urinary infections caused by bacteria harbored eight times as much of the peptide, the researchers report.

In a series of experiments, the researchers introduced Escherichia coli, which causes urinary tract infections, into the urethras of mice. The bacteria reached the bladder in greater numbers in animals genetically engineered to lack cathelicidin than they did in normal mice. Animals that lacked the peptide also developed more full-blown infections, lost more weight, and were more likely to die.

In mice that developed severe urinary tract infections, a backup defense system kicked in. Defensive cells called neutrophils, which carry their own supply of cathelicidin, flooded the urinary tract and delivered a second wave of the peptide, the team reports. Throughout the body, neutrophils typically prevent bacterial infections from spreading to the bloodstream.

The study is the first to show such an extensive role for cathelicidin in shielding the urinary tract from infection, Brauner says.

However, some bacteria have apparently grown resistant to cathelicidin. Brauner and her colleagues obtained 35 distinct strains of E. coli from people with urinary tract infections and tested cathelicidin against them in lab dishes. The strains taken from people whose infections had penetrated to areas upstream of the bladder were the most likely to be resistant to cathelicidin, the team reports.

While cathelicidin's microbe dragnet may not be perfect, the new research nevertheless offers "a sense of how aggressively cathelicidins are engaged to fend off invading bacteria,' says Michael Zasloff of Georgetown University Medical Center in Washington, D.C., writing in Nature Medicine. "Cathelicidin is prepared when needed, through a coordinated, explosive chain of events" within cells, he says.

"To figure that this little molecule plays such a big role in defending us against infections is amazing" according to Joost Oppenheim of the National Cancer Institute in Frederick, Md.

Companies have tried but failed to exploit such "homemade antibiotics" to create drugs, Oppenheim notes. The compounds are too toxic to take internally, he says.