"Whenever I urinate, it feels as if the urine had come to a boil inside my bladder."
This testimony by one woman with recurrent urinary tract infection (UTI) describes the burning pain that makes this widespread female complaint almost unbearable, though not life-threatening.
"One of the biggest problems with UTI," observed molecular microbiologist Scott Hultgren, at Washington University, in St. Louis, "is recurrent infections. A patient takes the antibiotic; the symptoms go away. But three weeks or three months later, she gets another infection."
UTI, also known as cystitis of the urinary bladder, afflicts upwards of 7 million women in the U.S. And one in 10 of them will have three to five recurrences per year. (See BioWorld Today, April 25, 1997, p. 1.)
Far and away the principal pathogenic perpetrator of UTI - by 80 percent - is the E. coli bacterium, which benignly populates the human gut. It makes up a hefty share of the solid matter in feces, which can opportunistically infect the female urinary tract via the vagina.
Such infective strains of E. coli are covered with sub-hair-like spiral tendrils known as pili. These slender whiskers terminate in antigenic molecules called adhesins, because they adhere to the cells lining the bladder's interior walls.
Hultgren is senior author of a paper in today's Science, dated Nov. 20, 1998, which lays bare (literally) the weirdly complex tactics by which E. coli infects the bladder, destroys its inner surface urothelial cells, and burrows into the organ's deeper layers to lie low, and strike again. The article is titled "Induction and evasion of host defenses by type 1-piliated uropathogenic Escherichia coli."
"In this paper," Hultgren told BioWorld Today, "we show that the bladder cell commits suicide when the bacteria bind to it. Somehow the pili attachment leads to activation of an apoptosis pathway. So, this is an example of the bladder cell killing itself for the good of the rest of the population.
"We discovered," Hultgren went on, "that this altruistic apoptotic-like pathway is involved in the bladder's innate defense. But what's interesting is that it's a double-edged sword. This binding event, which activates the innate defense, is absolutely critical in the ability of the bacteria to cause the disease."
What this leads to, as these cells die and slough off the bladder wall, is a mechanism to try to get rid of the attached bacteria. They shed into the previously sterile voided urine.
"One of the classic signs that a patient has a UTI," Hultgren said, "is when the doctor does a urine analysis, and sees massive amounts of exfoliated cells in the urine. Now we've discovered why that is."
His paper describes how the invading bacteria somehow manage, in some cases, to persist, rather than get washed away with the dead cells. "What they're able to do," he said, "is sidestep this massive exfoliation, and rebind to newly exposed layers underneath the superficial epithelium. Then, they're able to invade deeper into the tissue."
Cracking Enigma Of UTI: Recurrent Or Chronic?
Hultgren and his co-authors see this maneuver as a mechanism by which the pathogens are able to persist, even in the face of this exfoliation, and live on to cause recurrence of the UTI another day.
"For decades and decades," Hultgren observed, "the dogma has been that recurrent UTI infections are caused by de novo reinfection or reinoculation of the urinary tract. But our new data suggest a possible alternative: that, at least in some recurrent UTIs, instead of a reinoculation maybe the bacteria are able to persist chronically, perhaps at low levels, in the deeper levels of the epithelium, in an asymptomatic state. Then, occasionally, something causes them to flare up, and you get symptoms - what's classified now as recurrent infection, rather than a more chronic condition."
He and his co-authors inoculated two strains of infective E. coli into the bladders of mice. One was isolated from a UTI patient, the other a recombinant lab strain.
Autopsying the bladders of their mouse models revealed the various stages of the scenario the team had discovered - from binding to apoptosis to exfoliation to in-depth penetration. They studied these steps by ultra-high-resolution electron microscopy, using magnification upwards of 65,000 times.
"First of all," Hultgren recounted, "we obtained extremely high resolution images of the bacterial attachment - snapshots of E. coli binding to the walls of the bladder. Then, with those molecular snapshots in hand, we realized that we had discovered that the binding molecules of the pili tips are adhesins. We could clearly see the adhesins attaching to the bladder-cell receptors.
New Findings Presage Vaccines, Drugs
Hultgren is pursuing two therapeutic implications of these findings: a vaccine and a drug. His vaccine, which targets the antigenic adhesin molecule on the tips of E. coli pili, is under development by MedImmune Inc., of Gaithersburg, Md. It was tested last year and this on eight female monkeys in Sweden.
"We have currently completed these primate studies," MedImmune's director of immunology and molecular genetics, Solomon Langermann, told BioWorld Today. "They were successful, and we are now proceeding with development of our plans to hopefully initiate clinical trials next year."
He observed that Hultgren's findings in today's Science "strengthen the application of our vaccine, because they confirm in greater detail that the adhesins are binding to the mannose receptors - the uroplakin molecules on the bladder - so this really strengthens the position pf targeting that adhesin in terms of blocking the infection."
To which Hultgren added, "The idea of a vaccine would eliminate this hypothetical chronic state, and hopefully protect people from recurrent flare-ups. The other strategy we're working on is trying to develop compounds that would block the assembly of these adhesive pili. This would be a new class of antibiotic, which could prevent the entire pathogenic cascade. We're working on it with Siga Pharmaceuticals Inc., of Corvallis, Ore.," the location of New York-based Siga's laboratories.
Siga's director of drug discovery, molecular biologist Hal Jones, said that, under its license of Hultgren's technology, his company is working to develop a broad-spectrum small molecule - ideally to be taken orally - which would prevent the assembly of Gram-negative bacterial pili in general, and E. coli in particular. n