Enterotoxigenic Escherichia coli and Staphylococcus ruber It is responsible for hundreds of millions of infections worldwide each year and remains the leading cause of fatal diarrheal diseases, especially in children. Despite decades of research, scientists have yet to develop an effective vaccine against either pathogen. One major challenge is that the characteristics of the bacteria that vaccines typically target vary widely between strains.
Now, researchers at Washington University School of Medicine in St. Louis have identified a common biological vulnerability to these dangerous gut bacteria, raising the possibility of a single vaccine that protects against both.
The WashU Medicine team, working with collaborators at the University of Missouri and the International Center for Diarrheal Disease Research in Bangladesh, discovered that enterotoxigenic substances were present. Escherichia coli (main cause of traveler’s diarrhea) Staphylococcus ruberand several other disease-causing bacteria, rely on three closely related enzymes to invade the protective mucus layer of the intestines and establish infection.
Using samples from infected patients and volunteers exposed to the bacteria, the researchers showed that antibodies directed against common regions of these enzymes can neutralize all three. Antibodies prevent bacteria from crossing the intestinal mucus barrier by blocking enzymes.
The findings were published on June 15th. PNASsuggests that future combination vaccines may prevent multiple major causes 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.”
How do intestinal pathogens break through the body’s defenses?
Before intestinal pathogens can cause disease, they must first pass through the thick mucus layer that lines the intestines. This protective coating acts as a barrier, keeping harmful microorganisms away from your intestinal tissues and even helps to suppress your body’s beneficial bacteria.
Fleckenstein said this early stage of infection could provide an opportunity to stop the disease before it starts, without harming beneficial microorganisms.
Enterotoxigenic Escherichia coli (ETEC), which unlike harmless virus strains, causes gastrointestinal disease. Escherichia coli Commonly found in the intestines Staphylococcus ruber Closely related enzymes are used to cleave the proteins that give mucus its structure. If bacteria break through this barrier, they can release toxins that cause diarrhea.
Fleckenstein’s lab previously identified one of these enzymes that causes the disease. Escherichia coli. This enzyme, known as EatA, breaks down important structural components of intestinal mucus. New research reveals that two similar enzymes are produced, SepA and Pic. Staphylococcus ruber and other diarrhea-causing bacteria perform the same function.
Antibodies that block multiple pathogens
In collaboration with co-author Dr. Ali Elebedi and Professor Leo Loeb of the Department of Pathology and Immunology at WashU School of Medicine, Fleckenstein and his colleagues isolated antibodies from people in Bangladesh who had naturally contracted ETEC infection and from volunteers who were intentionally exposed to the bacteria in a controlled study.
The research team discovered that antibodies that can block EatA can also neutralize SepA and Pic. Antibodies are proteins produced by the immune system that recognize and bind to specific targets, helping the body eliminate threats.
To better understand how this protection works, structural biologists at the University of Missouri, including lead author and postdoctoral researcher David P. Buckley, Ph.D., used cryo-electron microscopy, a method that allows molecules to be rapidly frozen and imaged in great detail.
Their analysis revealed exactly where the most effective antibodies bind. These antibodies target regions shared by all three enzymes, explaining how a single antibody can override mucus-degrading mechanisms used by multiple pathogens. This discovery also provides vaccine developers with specific targets that can be used to stimulate protective antibody responses before infection occurs.
“This study demonstrates that EatA is a viable vaccine candidate that can provide protection against multiple pathogens,” said Dr. Zachary Bernsen, assistant professor of biochemistry at the University of Missouri and co-senior author of the study. “By identifying key regions of EatA that can be targeted by neutralizing antibodies that can inhibit enzyme function, we have established the basis for rational vaccine design. This is a major step toward developing effective therapeutics that have the potential to save many lives.”
Evidence from children in Bangladesh
This finding builds on previous research among children in Dhaka, Bangladesh. These studies showed that children who naturally produce antibodies against EatA are less likely to get sick, while children without those antibodies are at higher risk of infection.
Researchers say the need for an effective vaccine extends far beyond developing countries. Enterotoxigenic Escherichia coli It has been linked to a large-scale outbreak of food poisoning in the United States. Because it is difficult for many clinical laboratories to distinguish it from something harmless. Escherichia coli Strains and infections are often missed or underreported.
Fleckenstein also pointed out that there is a high reliance on antibiotics to treat these infections, increasing the problem of antibiotic resistance, which has the potential to spread globally.
Towards vaccine development
The research team is currently working towards developing a vaccine based on these findings.
“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 the spread before it spreads.”
This research was supported by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH), grant numbers R01 AI089894 and R01 AI126887, and the Department of Veterans Affairs, grant number 5I01BX001469-05. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or Department of Veterans Affairs.
