Enterotoxigenic E. coli and Shigella are responsible for hundreds of millions of infections worldwide each year and remain among the leading causes of fatal diarrheal disease, particularly in children. Despite decades of research, scientists have not yet developed effective vaccines against either pathogen. One major challenge is that the bacterial features typically targeted by vaccines vary widely between strains.
Now, researchers at Washington University School of Medicine in St. Louis have identified a biological vulnerability shared by these dangerous gut bacteria, raising the possibility of a single vaccine that could protect against both.
A team from WashU Medicine, working with collaborators at the University of Missouri and the International Centre for Diarrhoeal Disease Research in Bangladesh, found that enterotoxigenic E. coli (the leading cause of travelers' diarrhea), Shigella, and several other disease-causing bacteria depend on three closely related enzymes to penetrate the gut's protective mucus layer and establish infection.
Using samples from infected patients and volunteers who had been exposed to the bacteria, the researchers showed that antibodies directed against a common region of these enzymes can neutralize all three. By blocking the enzymes, the antibodies prevent the bacteria from crossing the intestinal mucus barrier.
The findings, published June 15 in PNAS, suggest that a future combination vaccine could potentially protect against multiple major causes of severe diarrhea.
"For something so common and so deadly to young children, it's striking that we still don't have a vaccine for either of these pathogens," said James M. Fleckenstein, MD, a professor of medicine in the Division of Infectious Diseases at WashU Medicine and co-senior author on the study. "What's exciting here is that we've found a kind of Achilles' heel or weak point they share that we might be able to target to protect against both."
How Gut Pathogens Break Through the Body's Defenses
Before they can cause disease, gut pathogens must first get through a thick mucus layer that lines the intestines. This protective coating acts as a barrier, keeping harmful microbes away from intestinal tissues and even helping keep the body's beneficial bacteria in check.
According to Fleckenstein, this early stage of infection may offer an opportunity to stop disease before it starts, without harming helpful microorganisms.
Enterotoxigenic E. coli (ETEC), which causes gastrointestinal illness unlike the harmless strains of E. coli commonly found in the gut, and Shigella use closely related enzymes to cut through the proteins that give mucus its structure. Once they break through this barrier, the bacteria can release toxins that trigger diarrhea.
Fleckenstein's laboratory previously identified one of these enzymes in disease-causing E. coli. The enzyme, known as EatA, breaks down a key structural component of intestinal mucus. The new study revealed that two similar enzymes, SepA and Pic, produced by Shigella and other diarrhea-causing bacteria, perform the same function.
Antibodies That Block Multiple Pathogens
Working with coauthor Ali Ellebedy, PhD, the Leo Loeb Professor in the WashU Medicine Department of Pathology & Immunology, Fleckenstein and colleagues isolated antibodies from people in Bangladesh who had naturally contracted ETEC infections as well as from volunteers intentionally exposed to the bacteria in controlled studies.
The team discovered that antibodies capable of blocking EatA could also neutralize SepA and Pic. Antibodies are proteins produced by the immune system that recognize specific targets and attach to them, helping the body eliminate threats.
To better understand how this protection works, structural biologists at the University of Missouri, including first author David P. Buckley, PhD, a postdoctoral research associate, used cryo-electron microscopy, a method that rapidly freezes molecules so they can be imaged in extraordinary detail.
Their analysis revealed exactly where the most effective antibodies bind. The antibodies targeted a region shared by all three enzymes, explaining how a single antibody can disable the mucus-degrading machinery used by multiple pathogens. The discovery also provides vaccine developers with a specific target that could be used to stimulate protective antibody responses before infection occurs.
"This study establishes EatA as a viable vaccine candidate capable of providing protection across multiple pathogens," said Zachary Berndsen, PhD, an assistant professor of biochemistry at the University of Missouri and co-senior author on the study. "By identifying the key regions of EatA that are targeted by neutralizing antibodies capable of inhibiting its enzymatic function, we've established a foundation for rational vaccine design -- a major advance toward development of effective therapeutics that have the potential to save many lives."
Source: ScienceDaily
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