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Worldwide, more than one million deaths occur each year due to diarrheal diseases that lead to dehydration and malnutrition. Yet no vaccine exists to fight or prevent these diseases, which are caused by bacteria like certain strains of E. coli. Instead, people with bacterial infections must rely on the body to adopt one of two defense strategies: kill the intruders or weaken the intruders but keep them around. If the body chooses to alter the bacteria, illness can occur without diarrhea, but the infection can still be transmitted, a process called asymptomatic carriage.
Now, Salk scientists have found that combining specific diets with pathogenic bacteria can create long-lasting immunity in mice without the costs of disease development, revealing a potential new vaccination strategy. Their findings, published in Scientists progress on June 23, 2023, to pave the way for the development of new vaccines that could promote immunity in people with diarrheal diseases and possibly other infections.
“We found that immunization against diarrheal infections is possible if we allow the bacteria to retain some of their pathogenic behavior,” says lead author Professor Janelle Ayres, Salk Institute Legacy Chair and Lead from the Molecular and Systemic Physiology Laboratory. “This idea could lead to the development of vaccines that could reduce symptoms and mortality, as well as protect against future infections.”
In 2018, Ayres’ lab examined how dietary interventions can create asymptomatic infection, which Ayres calls a cooperative relationship between the bacteria and the host (the person or animal the bacteria has infected) where the host has no symptoms. They found that an iron-rich diet allowed mice to survive a normally fatal bacterial infection without ever developing signs of illness.
The iron-rich diet increased unabsorbed sugar (glucose) in the mice’s intestines, which the bacteria could feast on. The excess sugar served as a “bribe” for the bacteria, keeping them full and incentivized not to attack the host.
This process produced long-term, asymptomatic infection with the bacteria, leading researchers to believe that the adaptive immune system (cells and proteins that “remember” infections) may be involved.
“Being able to generate long-lasting immunity against bacteria like C. rodentium or E. coli was not possible using established vaccination strategies. We wanted to understand what mechanism maintained this long-lasting immunity, so that we could use this mechanism to create an impactful solution to these diarrheal diseases,” says first author Grischa Chen, a former postdoctoral researcher in Ayres’ lab.
Researchers sought to understand how the body suppresses symptoms of infection, whether infection without symptoms can create long-term immunity, and whether this immunity is reproducible as a vaccination strategy.
The team compared mice on iron-rich and normal diets after C. rodentium infection to determine whether the diet had an impact on asymptomatic infection. Immediately after infection, mice fed an iron-rich diet showed no symptoms, while mice fed a normal diet did. All mice were then put on a normal diet to see if the asymptomatic infection would last.
Mice with a non-functioning adaptive immune system (the immune system that “remembers” previous infections), whether or not they had been on an iron-rich diet, could not continue to have a cooperative relationship with the bacteria. Although the iron-rich diet suppressed symptoms immediately after infection, the adaptive immune system was necessary for sustained cooperation. Importantly, mice with a functioning adaptive immune system had the disease without any symptoms, with long-lasting immunity, as evidenced by survival after reinfection after one month.
Ayres and his team concluded that an iron-rich diet alone can prevent bacteria from creating life-threatening symptoms in mice during an active infection. But a functioning adaptive immune system is necessary for immunity against future infection in the absence of dietary supplementation.
Some bacterial strains, if mutated enough, do not cause symptoms. To test whether such bacteria could produce long-lasting immunity, the team repeated their iron diet versus normal diet experiment in mice, but this time using bacteria that could cause disease and bacteria. which could not cause disease. They found that only mice given unmutated pathogenic bacteria were able to sustain immunity upon reinfection.
Scientists note that people should not consume large amounts of iron after reading this study. Their results are preliminary and need to be confirmed in human subjects.
The researchers hope their knowledge will provide a foundation for future research in humans and the creation of a vaccination regimen that protects and prevents against diarrheal disease.
Grischa Chen et al, Cooperation between physiological defenses and immune resistance produces asymptomatic carriage of a deadly bacterial pathogen, Scientists progress (2023). DOI: 10.1126/sciadv.adg8719. www.science.org/doi/10.1126/sciadv.adg8719