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By Sean Henahan, Access Excellence 

St. Louis, MO (April 25, 1997)  A new vaccine developed to prevent urinary tract infections could usher in an entirely new class of antibiotic therapies, report researchers.

Caption: Electron micrograph of E. coli showing hair-like appendages called pili. A protein at the pilus tip called an adhesin enables the bacterium to lock its pili onto the bladder wall, a critical first step in infection.

Researchers have developed a vaccine to prevent urinary tract infections caused by E. coli. The vaccine is based on a a protein called an adhesin. The new approach could offer a way around the growing problem of anti-biotic resistance.

"Antibiotic resistance is becoming more and more of a problem even simple infections like cystitis are getting harder to treat," says Scott J. Hultgren, Ph.D., associate professor of molecular microbiology at Washington University School of Medicine in St. Louis. "So it's becoming increasingly important to develop novel ways to fight infection. Vaccine development is one avenue to take." 

The experimental vaccine prevents E. coli from attaching itself to the urinary tract. E. coli - like many bacteria - is covered with fine hairs called pili, which have sticky tips.  Hultgren's group has shown that one of the proteins at the tip, an adhesin, fits into a receptor on the bladder lining. By locking its pili into these receptors, a bacterium can cling to the bladder like Velcro. Even a flood of urine fails to sweep it away. 

"This is a very basic principle that should be applicable to a wide range of bacterial infections, including middle-ear infections, pneumonia, meningitis, kidney infections and gonorrhea," Hultgren says. 

Adhesin-based vaccines offer a novel approach to ward off infectious disease. "The idea is very attractive because such a vaccine would give bacteria a double whammy - antibodies against the protein would both block attachment and mark bacteria for destruction by the immune system," Hultgren says. 

A recent analysis of bacterial samples from cystitis patients across the United States  found that FimH, the adhesin produced by the bladder-loving E. coli, hardly varies from strain to strain. Antibodies to FimH also cross-reacted with more than 95 percent of the strains and prevented binding to bladder cells. Therefore a single vaccine might prevent recurrent bladder infection, even if a succession of strains was involved. 

By removing the FimH gene from E. coli, the researchers also proved that a bacterium without sticky pili is as useless. "So the binding event is absolutely critical to the bacterium's ability to cause disease," Hultgren says. 

Painstaking studies of pilus assembly allowed Hultgren's team to produce correctly folded adhesin that could be used as vaccine. "This is a nice example of how basic science can promote advances in clinical care," Hultgren says. 

Over the past decade, his group has shown that the pilus assembly line begins when adhesin molecules and other components are shipped to the periplasmic space - the region between the two membranes that surround E. coli. Boomerang-shaped proteins called chaperones latch onto these building blocks and also mold adhesin into shape. When the chaperone-adhesin complexes reach the outer membrane, the chaperones release their cargo to tunnel-shaped proteins called ushers - mini spaghetti machines that assemble and extrude pili to the bacterial surface. 

To obtain FimH for purification, the researchers stepped up adhesin production and derailed the assembly process. They attached "on switches" to chaperone and adhesin genes, inserted the resulting complexes into E. coli, and deleted the usher gene. The product is a bacterium that overproduces chaperones and correctly folded adhesin molecules. These complexes accumulate in the periplasm, staying soluble instead of gluing themselves onto pilus tips. "So by getting rid of the ushers, you end up with chaperone-adhesin complexes that are easy to purify in large amounts," Hultgren says. 

Further studies showed that the adhesin triggers a strong, long-lasting immune response when injected into mice. The researchers also applied the resulting antibodies to cultured cells from the bladder lining, finding that they prevent E. coli from binding to the cells. To see if the vaccine can have the same effect in live animals, they inoculated E. coli into the urinary tract of mice. The animals developed full-blown bladder infections - unless the E. coli lacked the gene for FimH. But vaccination with FimH allowed normal mice to resist infection  the linings of their bladders had 100 to 1,000 times fewer bacteria than those of unvaccinated mice. The anti-adhesin antibodies also prevented bladder infection when they were introduced into the bloodstream via the abdominal cavity.

Because Hultgren's group has shown that almost 30 different kinds of adhesins are assembled via the chaperone-usher pathway, the researchers hope to develop additional products to fight infectious disease. "Dissecting out the molecular details of these pathways has allowed us to create advanced technologies  for developing agents that block the assembly of adhesive pili," Hultgren says. "These would represent a whole new class of antibiotics - one of the first in 20-to-30 years." 

The research appeared in the April 25, 1997 issue of Science.

Related information on the Internet 

AEŻACTIVITY: E.coli and Bacteria

AE:ŻE.Coli Test

Dr. Hultgren's Biography

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