Biotechnology

All immunity, no symptoms


LA JOLLA (June 23, 2023)—Worldwide, more than one million deaths occur each year from diarrheal diseases that lead to dehydration and malnutrition. However, there is no vaccine to fight or prevent this disease, which is caused by bacteria such as certain strains E. coli. Conversely, people with bacterial infection must rely on the body adopting one of two defense strategies: kill the intruder or damage the intruder but defend it. If the body chooses to destroy the bacteria, then the illness can occur without diarrhea, but the infection can still be transmitted—a process called asymptomatic conveyance.

LA JOLLA (June 23, 2023)—Worldwide, more than one million deaths occur each year from diarrheal diseases that lead to dehydration and malnutrition. However, there is no vaccine to fight or prevent this disease, which is caused by bacteria such as certain strains E. coli. Conversely, people with bacterial infection must rely on the body adopting one of two defense strategies: kill the intruder or damage the intruder but defend it. If the body chooses to destroy the bacteria, then the illness can occur without diarrhea, but the infection can still be transmitted—a process called asymptomatic conveyance.

Now, Salk scientists have found that pairing a special diet with disease-causing bacteria can create lasting immunity in mice without the cost of developing the disease, revealing the potential of a new vaccination strategy. Their findings, published in Science Advances on June 23, 2023, paving the way for the development of a new vaccine that can boost immunity for people with diarrhea and possibly other infections.

“We found that immunization against diarrheal infections is possible if we allow the bacteria to retain some of its disease-causing behavior,” said senior author Professor Janelle Ayres, Chair of the Salk Institute’s Legacy and head of the Laboratory of Molecular and Systems Physiology. “These insights could lead to the development of vaccines that can reduce symptoms and death, and protect against future infections.”

In 2018, Ayres’ lab looked at how dietary interventions can create asymptomatic infections, which Ayres calls a cooperative relationship between bacteria and host (a person or animal that has been infected by the bacteria) in which the host does not develop any symptoms. They found that an iron-rich diet allowed the mice to survive a normally deadly bacterial infection without ever showing signs of illness or disease. A diet high in iron increases unabsorbed sugar (glucose) in the rat intestine, which is bacteria can party. Excess sugar serves as a “bribe” for bacteria, satiating them and providing an incentive not to attack the host.

This process results in long-term asymptomatic infections with bacteria, leading researchers to believe that the adaptive immune system (cells and proteins that “remember” infections) may be involved.

“Being able to produce lasting immunity against bacteria like C. rodents or E. coli it is not yet possible to use established vaccination strategies. We wanted to find out what mechanisms maintain this enduring immunity, so that we can use those mechanisms to create solutions that have an impact on these diarrheal diseases,” said first author Grischa Chen, a former postdoctoral researcher in Ayres’ lab.

Researchers are moving to find out how the body suppresses symptoms of infection, whether asymptomatic infection can create long-term immunity, and whether that immunity can be reproduced as a vaccination strategy.

The team compared rats on an iron-rich diet and normal thereafter C. rodents infection to see if diet has an impact on asymptomatic infection. Immediately after infection, mice fed an iron-rich diet were asymptomatic, whereas mice fed a normal diet had symptoms. All mice were then put on a normal diet to see if asymptomatic infection would persist.

Mice with nonfunctional adaptive immune systems (immune systems that “remember” previous infections), regardless of whether they had been on an iron-rich diet, were unable to continue to maintain a cooperative relationship with bacteria. Although an iron-rich diet suppresses symptoms immediately after infection, an adaptive immune system is required for lasting cooperation. Importantly, mice with a functional adaptive immune system have asymptomatic, long-lasting disease immunity, as demonstrated by survival after reinfection after one month.

Ayres and team concluded that an iron-rich diet alone prevented the bacteria from creating lethal symptoms in the mice during an active infection. But a functional adaptive immune system is necessary for immunity against future infections in the absence of dietary supplements.

Some strains of the bacteria, if sufficiently mutated, cause no symptoms. To test whether the bacteria could produce lasting immunity, the team repeated the iron-diet versus normal-diet experiment in mice, but this time using disease-causing bacteria and non-disease-causing bacteria. They found that only mice that received the unmutated disease-causing bacteria were able to support immunity after reinfection.

The scientists noted that people should not consume large amounts of iron after reading this study. Their findings are preliminary and need to be confirmed in human subjects.

The researchers hope their insights will provide a basis for future research in humans and the creation of vaccination regiments that protect against and prevent diarrheal disease.

Other authors include Natalia R. Thorup, Abigail J. Miller, and Yao-Cheng Li of Salk.

This work was supported by the National Institutes of Health (DPI AI144249, R01AI4929), NOMIS Foundation, DARPA Yong Faculty Award (YFA15 D15AP00097), Hillblom Foundation Fellowship Grant, Chapman Foundation, the Helmsley Charitable Trust,

About the Salk Institute for Biological Studies:

Unlocking the secrets of life itself is the driving force behind the Salk Institute. Our team of world-class award-winning scientists pushes the boundaries of knowledge in fields such as neuroscience, cancer research, aging, immunobiology, plant biology, computational biology and many more. Founded by Jonas Salk, developer of the first safe and effective polio vaccine, the Institute is an independent non-profit research organization and an architectural landmark: small by choice, intimate by nature, and fearless in the face of any challenge. Learn more at www.salk.edu.




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