E. coli vaccine one step closer

Memphis investigators see promising results in lab tests on animals

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From a basement laboratory in the Memphis medical center comes new hope for a vaccine to protect against a strain of the E. coli bacteria that kills thousands of youngsters every year and sidelines millions of travelers.

In a recent online edition of the scientific journal Nature, investigators from the Memphis Veterans Medical Center and the University of Tennessee Health Science Center described promising early results for two experimental vaccines. Both were largely effective at preventing E. coli from gaining a foothold in the digestive tracts of mice. "There is still a tremendous amount of work to be done" to create a human vaccine, cautioned Dr. James Fleckenstein, the study's senior author.

The vaccines were designed to block the infection by preventing a protein at the end of the E. coli's whip-like flagella from attaching to a second protein, known as EtpA. EtpA is secreted by the E. coli bacteria and apparently plays a role in helping the bug stick to the intestinal tract of the unsuspecting patient. The interaction between the two proteins is a key step in the infection process.

Fleckenstein called the discovery of the protein interaction the most promising vaccine target in his nearly 20 years of research. Fleckenstein is a UT Health Science Center associate professor of medicine and molecular sciences. He is also an investigator at the Memphis VA.

"It does look like a very promising lead," said Dr. George Munson, of the University of Miami's Miller School of Medicine. Munson, an assistant professor of microbiology and immunology, wasn't part of research described in the recent publication.

The global push to develop a vaccine to protect against this E. coli infection began years ago. But Munson said Fleckenstein's group has identified two new targets. "It applies possible new routes to a safe and effective vaccine," he explained.

EtpA, which Fleckenstein's laboratory identified in 2006, also apparently plays a role in other diarrheal diseases, Fleckenstein said. That raises hope any potential vaccines targeting EtpA will prove useful against other infections.

The publication comes amid heightened interest in combating this strain of E. coli. While various strains of the bug live harmlessly or even helpfully in the human gut, Fleckenstein's work focuses on one of the bad actors.

It is formally known as enterotoxigenic Escherichia coli, or ETEC. Found most commonly in developing countries where drinking water is contaminated by fecal material, ETEC is a major cause of traveler's diarrhea. It is also blamed for roughly 500,000 deaths annually, primarily due to dehydration among patients age 5 and younger.

"If we had clean water in developing countries, we wouldn't have a need for a vaccine," Fleckenstein said. He said U.S. outbreaks of the infection are also increasing, likely due in part to an increasingly global food supply.

In 2008, the Bill & Melinda Gates Foundation earmarked $50 million to support development of vaccines against ETEC and another bacteria linked to deadly diarrhea in youngsters.

ETEC is also among the bacteria whose genetic blueprints are being deciphered. Of the dozens of different versions of ETEC, Fleckenstein said three have been decoded. Such detailed genetic information will likely identify additional vaccine targets, he said.

Serendipity played a role in the Memphis group's latest advance.

Fleckenstein's laboratory had been trying without success to purifying EtpA. EtpA is a sticky protein that helps E. coli adhere to the small intestines and begin to spread. Fleckenstein's laboratory discovered EtpA in 2006. "It acts as a molecular glue," he said.

They eventually sent samples to the laboratory of Dr. George M. Hilliard at UT Health Science Center. His analysis showed EtpA was bound with flagellin, a small protein at the tip of ETEC's flagella. Memphis investigators now believe that binding plays a key role in E. coli infections.

Eventually Fleckenstein's group used both EtpA and flagellin as the basis of three different experimental animal vaccines.

Fleckenstein said experimental vaccines that tapped the flagella proteins triggered the strongest immune response in animals. But he said additional work is needed before they are ready for human trials.

"We are trying to tease out the parts of the flagella that will stimulate an immune response without causing problems" for humans, he said. Investigators are also wary of causing problems by inadvertently killing off helpful E. coli strains.

By The Numbers

ETEC, or enterotoxigenic Escherichia coli, is a bacterial infection spread primarily through unclean drinking water.

It is blamed for about 500,000 deaths annually. The victims are usually infants and toddlers living in developing countries.

The bug also causes millions of cases of traveler's diarrhea annually.



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