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| |  New Strategy For Fighting Infection Proves Successful In Mice St. Louis -- April 24, 1997 -- Researchers in Maryland and Missouri have found a sticky solution to the problem of how to ward off infection in an era of antibiotic resistance. The study, reported in today's issue of the journal Science, describes a strategy to prevent bacteria from getting a toehold on tissues and therefore from causing infection. The researchers developed a vaccine to prevent urinary tract infections caused by E. coli. The vaccine is a protein called an adhesin. "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." Unlike antibiotics, which usually are given after bacteria have set up shop, the vaccine prevents E. coli from getting a foot in the door. "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. The technology for producing the vaccine was developed by Hultgren's team at Washington University School of Medicine in St. Louis. The product was tested by Solomon Langermann, Ph.D., and colleagues at MedImmune Inc., a biotechnology company in Gaithersburg, Md. Bladder infection or cystitis affects mostly women, whose anatomy allows bacteria from feces to be swept into the urinary tract. At least half of American women have this itchy and painful problem once during their lives, and up to 10 percent suffer three to five infections per year. The disorder accounts for 7 to 8 million visits to physicians and hospitals each year at a cost of more than $1 billion. 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. 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. Langermann and colleagues analyzed bacterial samples from cystitis patients across the United States. They 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 as a Post-it Note without gum. "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. The FimH vaccine is being tested on monkeys at the Karolinska Institute in Sweden by Staffan J. Normark, M.D., Ph.D., who identified adhesins as minor components of pili in 1987. If the monkey trials are successful, the vaccine will be tested in humans. The human bladder contains the same receptor as that of mice. 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." This study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and by MedImmune.
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