see press release below:
FOR IMMEDIATE RELEASE: 15 JANUARY 1998
SCIENCE MAGAZINE HAS LIFTED THE EMBARGO
Contact: Linda Sage
Washington University School of Medicine
Hurdle in Ulcer Vaccine Development
St. Louis, (Date) -- The bacterium that causes most peptic ulcers clings to the
stomach wall by locking onto specific receptors on cells in the gastric lining.
Collaborators in Sweden and the United States now have identified and
isolated a bacterial protein that allows the microbe to cling.
"With this attachment protein in hand, it eventually should be possible to
develop a vaccine against peptic ulcers and gastric cancer," says Thomas
Borén, D.D.S., Ph.D., an assistant professor of oral biology at Umeĺ
University in Sweden. Borén headed the research team, which published its
findings in the Jan. 16 issue of Science.
When Borén was at Washington University School of Medicine in St. Louis in
1993, he discovered that Helicobacter pylori, the bacterium that infects the
gastric lining, attaches to a carbohydrate called the Lewis b (Leb) blood
group antigen. This antigen is found on the red blood cells of people with type
O blood, but it also occurs on the gastric lining. "So the bacterium prefers to
bind to receptors present in blood group O individuals," Borén says. "And we
have found that this binding property is highly associated with H. pylori
isolated from patients with ulcer disease."
Most of the world's population is infected with H. pylori, though the
prevalence is higher in developing countries and in regions of poverty in the
Western world. The bacterium probably is spread by unclean fingers and
hands and contaminated food and water. More than one-third of Americans
have this infection, and about 20 percent of them eventually develop peptic
ulcer disease. Most gastric cancers also occur in people with current or past
H. pylori infections. Although stomach cancer is rare in the United States, it is
the most common male cancer in some parts of the world.
"So there's a real need for new ways to prevent or cure H. pylori infection,"
says Douglas E. Berg, Ph.D., the American member of the research team. "In
places where people are at high risk for infection, such as shanty towns in
developing countries, reinfection after curing with antibiotics is commonplace.
So an effective, cheap vaccine that boosted immunity after every exposure
would be incredibly important." Berg is the Alumni Professor in Molecular
Microbiology and a professor of genetics at Washington University School of
Medicine in St. Louis.
In the study, the collaborators focused on the microbial part of the interaction
between H. pylori and Leb -- the second half of the Velcro sandwich. The
Swedish group showed that a protein they located on the surface of H. pylori
-- BabA (blood group antigen binding adhesin) -- attaches to the Leb antigen.
They also found that H. pylori strains from different parts of the world had
adhesins that were the same size and had the same initial 20 amino acids.
"Biologically conserved bacterial surface proteins have great potential as
vaccine candidates," Borén says.
If part of the BabA molecule could be used as a vaccine, it would prime the
immune system to attack similar proteins, preventing H. pylori from clinging to
the gastric lining. Dislodged as the stomach churns or empties, the bacterium
would be less able to deliver toxic products to human tissue and therefore less
likely to cause disease.
To find the BabA protein, Borén's group invented a clever technique called
ReTagging (Receptor Activity Directed Affinity Tagging). First, the
researchers attached several Leb molecules to a large protein called albumin,
creating a structure that looked like a potato stuck with toothpicks. Then they
added a Y-shaped "toothpick" with biotin (actually a vitamin) on one tip. By
mixing these molecular potatoes with an H. pylori suspension and exposing
the mixture to ultraviolet light, they chemically linked the Y toothpick to
whatever had bound to their synthetic Leb receptor. Using special chemical
reagents, they then snapped the Y toothpick off the potato, leaving part of it
stuck to the bacterium. In this way, they added a biotin label to the protein
that had bound to Leb.
To isolate this protein, the researchers ground up the tagged H. pylori and
added magnetic beads that had been coated with avidin, a protein that binds
tenaciously to biotin. The avidin attracted the biotin out of the mixture along
with the sought-after protein. After pulling out the beads with a magnet, the
researchers removed the bacterial protein.
After determining part of the amino acid sequence of this protein, Borén's
group deduced the type of DNA sequence that could encode it. The
researchers then chemically synthesized pieces of DNA with that sequence to
serve as a primer in a powerful technique called PCR (the polymerase chain
reaction). This allowed them to recover the entire gene from the bacterium.
But instead of finding one such gene, they found a complex family, which
included two closely related members.
To determine which gene was functional, one of Borén's students, Johan
Ögren, spent the spring of 1997 in Berg's lab in St. Louis. He and Dangeruta
Kersulyte, a research associate in molecular microbiology at Washington
University School of Medicine, inactivated each of the two related genes to
see which one was critical for adhesion. Only the loss of the gene called
babA2 prevented the bacterium from binding to Leb.
"We propose that the protein product of this gene, BabA, allows H. pylori to
stick to the gastric epithelium and play a critical role in the efficient delivery of
factors that directly damage gastric tissues," Borén says.
Thomas Borén can be reached at: Thomas.Boren@oralbio.umu.se
Douglas Berg can be reached at: 314-286-0119
The work was supported by grants from the Swedish Society of Medicine,
Lion's Cancer Research Foundation, Umeĺ University, the Magnus Bergvall
Foundation, the Swedish Medical Research Council, the Swedish Society for
Medical Research, the Royal Swedish Academy of Sciences, the Umeĺ
University-Washington University Scientific Exchange Program, the National
Institutes of Health and the American Cancer Society.
Ilver D, Arnqvist A, Ögren J, Frick I-M, Kersulyte D, Incecik ET, Berg DE,
Covacci A, Engstrand L, Borén T.
Helicobacter pylori Adhesin Binding Fucosylated Histo-Blood Group
Antigens Revealed by ReTagging.
Science, vol. 279, Jan. 16, 1998.
Added on Date: 17:56:51 1/15/98
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