Diarrheal diseases that cause dehydration and malnutrition account for more than a million deaths annually worldwide. However, there is no vaccine to combat or prevent these diseases, which are brought on by certain E. coli strains. Instead, people with bacterial infections must rely on one of two body defenses: Keep the intruders around but kill or disable them. A process known as asymptomatic carriage allows the infection to spread without the need for diarrhea if the body decides to disable the bacteria.
The Salk researchers have now discovered a novel vaccine strategy by combining disease-causing bacteria in mice’s diets to produce long-lasting immunity without the risk of disease. Their findings, which were published on June 23, 2023, in Science Advances, open the way for the creation of new vaccines that might boost immunity in people who have diarrheal diseases and possibly other infections.
Senior author Professor Janelle Ayres, Salk Institute Legacy Chair and head of the Molecular and Systems Physiology Laboratory, states, “We discovered that immunization against diarrheal infections is possible if we allow the bacteria to retain some of its disease-causing behavior.” Vaccines that can both prevent future infections and lessen symptoms and mortality may be developed as a result of this insight.”
“We discovered that allowing the bacteria to retain some of its disease-causing behavior allows us to immunize against diarrheal infections. This knowledge may lead to the creation of vaccinations that minimize symptoms and mortality while also protecting against future infections.”
Professor Janelle Ayres, Salk Institute Legacy Chair and head of the Molecular and Systems Physiology Laboratory.
In 2018, the research conducted by Ayres’s group examined how dietary interventions can result in an asymptomatic infection, or what Ayres refers to as a cooperative relationship between the bacteria and the host (the person or animal that the bacteria have infected), in which the host does not exhibit any symptoms. They discovered that mice could survive a normally fatal bacterial infection on a diet high in iron without ever showing any signs of illness or disease.
The bacteria could feast on the mice’s intestines for unabsorbed sugar (glucose) from the high-iron diet. The bacteria received a “bribe” from the excess sugar, which kept them full and encouraged them not to attack the host.
The adaptive immune system—cells and proteins that “remember” infections—may have been involved, as this process resulted in a long-term, asymptomatic infection with the bacteria.
“Using established vaccination strategies, it has not been possible to generate lasting immunity against bacteria like C. rodentium or E. coli. Grischa Chen, the first author and a former postdoctoral researcher in Ayres’ lab, says, “We wanted to figure out what mechanism was sustaining this lasting immunity, so we could use that mechanism to create an impactful solution to these diarrheal diseases.”
The goal of the research was to determine how the body suppresses symptoms of infection, whether infection without symptoms can result in long-term immunity, and whether this immunity can be replicated as a vaccination strategy.
After being infected with C. rodentium, the team compared mice fed normal and iron-rich diets to see if the diet affected the symptomless infection. Mice fed a diet high in iron experienced no symptoms immediately after infection, whereas mice fed a diet with no iron experienced symptoms. After that, all of the mice were fed a normal diet to see if the infection lasted.
Mice with nonfunctional versatile resistant frameworks (the safe framework that “recalls” past diseases), whether or not they had ever experienced an iron-rich eating routine, couldn’t keep on keeping a helpful connection with the microbes. The adaptive immune system was required for long-term cooperation, even though the iron-rich diet reduced symptoms immediately following infection. Importantly, the disease did not show any symptoms in the mice with functional adaptive immune systems, and they had lasting immunity, as evidenced by their ability to survive a month after being reinfected.
Ayres and his team came to the conclusion that only a diet high in iron can keep bacteria from killing mice with active infections. However, in the absence of dietary supplements, immunity against subsequent infections requires a functioning adaptive immune system.
If sufficiently mutated, some bacterial strains do not cause symptoms. The team repeated their iron-diet versus normal-diet experiment on mice, but this time they used bacteria that could cause disease and bacteria that could not cause disease to see if these bacteria could produce lasting immunity. They discovered that upon reinfection, only mice that received unmutated disease-causing bacteria were able to support immunity.
After reading this study, the scientists advise that people not consume a lot of iron. Their preliminary findings will need to be verified with human subjects.
The researchers hope that their findings will serve as a foundation for subsequent research on humans and the development of a vaccination regimen that guards against diarrheal diseases.
More information: Grischa Chen et al, Cooperation between physiological defenses and immune resistance produces asymptomatic carriage of a lethal bacterial pathogen, Science Advances (2023). DOI: 10.1126/sciadv.adg8719. www.science.org/doi/10.1126/sciadv.adg8719
