Public Release: 

Hultgren Receives Prestigious Eli Lilly Award

Washington University School of Medicine

St. Louis, Feb. 25, 1998 -- Scott J. Hultgren, Ph.D., an associate professor of molecular microbiology at Washington University School of Medicine in St. Louis, will receive the Eli Lilly and Company Research Award from the American Society of Microbiology. The award recognizes basic research of unusual merit in the fields of microbiology and immunology by an investigator under age 40. The society pays special attention to originality and independence of thought.

"Scott Hultgren was considered by a panel of experts to be the most outstanding young microbiologist in the world because of the work he has done on organisms that are important in disease," says Stanley Falkow, Ph.D., president of the American Society of Microbiology and professor of microbiology and immunology at Stanford University School of Medicine. "He has set a paradigm for approaching structure-function studies in microorganisms."

Hultgren will receive the award plus a $5,000 cash prize during the society's annual meeting in May in Atlanta, Ga. He also will deliver the 1998 Eli Lilly Award lecture. The award is sponsored by Eli Lilly and Company, a global research-based pharmaceutical company headquartered in Indianapolis, Ind.

"I'm very pleased to receive this honor because it's one of the most prestigious awards in our field for younger investigators," Hultgren says. "And I'm honored to be put on the same list as the previous recipients, which include many distinguished microbiologists. I also have had the great fortune to work with extremely talented and dedicated graduate students, postdoctoral fellows and a research technician at Washington University. This award recognizes their outstanding achievements."

Hultgren, who came to the School of Medicine in 1989, studies ways in which bacteria attach to human tissue, a key event in the onset of disease. As a model system, he works with E. coli strains that infect the urinary tract. "Our strategy is to decipher the molecular basis of how bacteria cause disease and to use this information to design vaccines and novel antibacterial therapeutics," Hultgren says. "There is an urgent need for such products now that bacterial infections are becoming increasingly more difficult to treat due to the rising tide of antibiotic-resistant microbes."

Like many other bacteria, E. coli attaches to host tissue with sticky hairs. The hairs, or pili, are sticky because their feathery tips contain a protein called an adhesin, which fits into receptors in the urinary tract like keys into locks. Anchored in place, the bacterium can multiply rather than being washed away by the stream of urine.

Combining genetic manipulations with cell biology, protein chemistry, high-resolution electron microscopy and x-ray crystallography, Hultgren and colleagues are following three lines of research. First, they are determining the 3-D structure of the adhesin, hoping to find out how the protein's shape enables it to interact with host receptors. Second, they are investigating the consequences of this interaction and the cross-talk that switches on genes in both pathogen and host.

In the third program, Hultgren's team is studying the structure, function and assembly of E. coli P and type 1 pili, whose tips contain adhesins called PapG (on P pili) and FimH (on type 1 pili). For many years, researchers have been trying to purify these proteins for use as vaccines against urinary tract infections, but without success. Hultgren and colleagues have succeeded because they uncovered and made use of key facts about pilus assembly.

During nine years of painstaking research, the group discovered that a protein called a chaperone plays a critical role in molding pilus subunits and adhesins into their correct 3-D shapes and transporting them to the membrane that surrounds the bacterial cell. Another protein, called an usher, extrudes adhesin-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 Institute for six months as the recipient of a Nobel Fellowship, awarded by the Nobel Committee. The institute is located in the Karolinska Institute in Stockholm, Sweden. And on April 16, the Academy of Science of St. Louis will give Hultgren the 1998 Innovation Award. The award is presented to a scientist under age 40 who exhibits great potential and accomplishment.

Hultgren was born in Michigan City, Ind., and he obtained his bachelor's degree from Indiana University in Bloomington in 1981. After receiving his doctorate from Northwestern University in Chicago in 1988, he became a postdoctoral fellow at Umeå University in Sweden.

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