Bacteria that produce intestinal toxins Escherichia coli and Staphylococcus ruber Together, they cause hundreds of millions of infections each year and are one of the leading causes of diarrheal deaths, especially in children. Decades of vaccine development efforts have been inadequate, in part because the targets of conventional vaccines vary widely from strain to strain.
A new study from Washington University School of Medicine in St. Louis points out that these enteric pathogens have common biological characteristics that could lead to a vaccine that protects against both.
Researchers at WashU Medicine, along with collaborators at the University of Missouri and the International Center for Diarrheal Disease Research in Bangladesh, are investigating the effects of enterotoxigenic substances. Escherichia coli (main cause of traveler’s diarrhea) Staphylococcus ruber and other diarrhea-causing pathogens rely on three closely related enzymes to cross the protective mucus layer of the intestines and cause infection. Based on samples from infected patients and volunteers exposed to the bug, the research team showed that antibodies targeting a shared region of one of these enzymes could neutralize all three biomolecules and block the bacteria from crossing the intestinal mucus barrier.
The results, published June 15 in PNAS, demonstrate the potential of a single combination vaccine against a major cause of severe diarrhea.
“For a disease so common and so deadly for young children, it is surprising that there is still no vaccine for either of these pathogens,” said James M. Fleckenstein, MD, professor in the Division of Infectious Diseases at WashU Medicine and co-senior author of the study. “What’s interesting here is that we’ve found some sort of Achilles heel or common weakness that we might be able to target to protect against both.”
shared vulnerabilities
To cause disease, enteric pathogens must first penetrate the thick layer of mucus that coats the intestines and keeps even the body’s healthy resident bacteria at bay. Overcoming this barrier is a critical early stage of infection, Fleckenstein said, and is the point where harmful bacteria can be stopped without interfering with beneficial microorganisms. Enterotoxigenic Escherichia coli (ETEC) – So named because, unlike other strains, it causes gastrointestinal illness. Escherichia coli It’s harmless – and Staphylococcus ruber It manages this task using closely related enzymes that cleave key proteins in intestinal mucus. If bacteria break through the barrier, they can carry out toxins that cause diarrhea.
Fleckenstein’s lab identifies for the first time one of the enzymes that causes diarrhea Escherichia coliIt is appropriate to devour the main structural component of mucus, called EatA. The research team has now shown that two related enzymes, SepA and Pic, are produced. Staphylococcus ruber and several other diarrhea-causing bacteria perform the same mucus-destroying function.
Co-author Dr. Ali Elebedi, Professor Leo Loeb of the Department of Pathology and Immunology at the University of Washington School of Medicine, Fleckenstein and colleagues isolated antibodies from patients in Bangladesh who were naturally infected with ETEC and from volunteers who were intentionally infected with the bacteria in a control study. They found that antibodies that block EatA also neutralized SepA and Pic. Antibodies are proteins produced by the immune system to recognize and lock onto specific targets so that they can be destroyed.
Structural biologists at the University of Missouri, including lead author and postdoctoral researcher Dr. David P. Buckley, used cryo-electron microscopy, a technique that flash-freezes molecules to image them in detail, to pinpoint where the most effective antibodies bind to enzymes. This spot turned out to be a common area for all three. This explains how a single antibody can override the mucus-degrading machinery of multiple pathogens. It also gives vaccine designers precise targets for producing vaccines that encourage the immune system to produce such antibodies and be ready in case of infection.
This study established EatA as a viable vaccine candidate that can provide protection against multiple pathogens. By identifying key regions targeted by neutralizing antibodies that can inhibit the enzymatic function of EatA, we established the basis for rational vaccine design. This is a major step towards developing effective treatments that could potentially save many lives. ”
Dr. Zachary Berntsen, assistant professor of chemistry at the University of Missouri and co-senior author of this study
The project builds on previous research in children in Dhaka, Bangladesh, which showed that children who naturally produce antibodies to EatA tend to be protected from disease, while those without antibodies are more likely to get sick.
The need for vaccines to prevent these infectious diseases is not limited to developing countries. Enterotoxigenic Escherichia coli Caused large-scale food poisoning outbreaks in the United States and difficult to distinguish from harmless ones Escherichia coli Cases often go unrecognized in most clinical laboratories. Fleckenstein noted that reliance on antibiotics to treat these infections also promotes antibiotic resistance, which ignores national borders.
The team is currently working towards developing a vaccine.
“These bacteria have evolved with us and have become very good at getting past our defenses,” Fleckenstein says. “If we can stop that first step, we have a chance to stop these infections before they spread.”
sauce:
Washington University in St. Louis
Reference magazines:
Mr. Buckley, D.P.; others. (2026). human enterotoxigenic Escherichia coli (ETEC) infection induces antibodies that broadly neutralize the mucinase of the pathogenic virus. Escherichia coli and Staphylococcus ruber. Proceedings of the National Academy of Sciences. DOI: 10.1073/pnas.2614012123. https://www.pnas.org/doi/10.1073/pnas.2614012123
