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Hultgren Receives Prestigious Eli Lilly Award

dhesin-tipped hairs onto the cell surface. Before these studies, little was known about how bacteria transport proteins to their surface, where disease-causing factors typically are displayed.

By removing the usher gene and turning up the FimH gene, Hultgren produced E. coli that make large amounts of correctly folded adhesive protein. In the absence of usher, this protein remains inside the bacterium, from where it can be isolated. FimH purified by Hultgren's team recently underwent successful vaccine trials in mice at MedImmune Inc., a biotechnology company in Gaithersburg, Md. Human trials should begin later this year.

The vaccine primes the immune system to recognize FimH on invading bacteria. The resulting antibodies bind to FimH, capping the tips of the hairs and preventing them from sticking to receptors in the bladder. In the MedImmune trials, mice infected with E. coli did not succumb to disease. "This basic principle should be applicable to many infections, including meningitis, middle-ear infections, pneumonia, kidney infections and gonorrhea," Hultgren says.

The researchers also are testing inhibitors of the chaperone protein. Without this essential link in the assembly line, E. coli cannot make pili and therefore can no longer colonize the urinary tract or cause disease. The inhibitors therefore may prove useful as antibiotics against bacteria that already have a toehold in the urinary tract. Discovering how the chaperone binds to its cargo and molds it into shape is key to this project.

"Our ambition is to determine the structures and functions of all of the components involved in microbial attachment so we'll have a blueprint for developing novel antimicrobial therapeutics and strategies," Hultgren says.

Hultgren has received three other recent honors. In 1997, he was awarded an honorary doctorate from Umeå University in Sweden. Next summer, he will go to the Medical Nobel
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Contact: Linda Sage
sage@medicine.wustl.edu
314-286-0119
Washington University School of Medicine
25-Feb-1998


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