New research may have solved a mystery surrounding Crohn’s disease, a type of inflammatory bowel disease where immune defenses meant to attack invading microbes mistakenly target the body’s digestive tract. Norovirus is a common infection that causes vomiting and diarrhea. It is also one of many viruses and bacteria thought to trigger the onset of disease in people with Crohn’s disease, but the field is unclear why.
Norovirus is a highly contagious virus that causes vomiting and diarrhea. Anyone can become infected and sick with norovirus, and outbreaks are common. You may hear norovirus disease referred to as “food poisoning”, “stomach bug”, or “stomach flu”. Although noroviruses are the leading cause of foodborne illnesses, other germs and chemicals can also cause foodborne illnesses.
A clue appeared when previous studies found that a certain genetic change (mutation) is present in most people with the condition. This genetic mutation makes the cells of the intestinal mucosa more vulnerable to damage. However, the mystery was deepened again when it was learned that half of all Americans have this same risk-conferring genetic mutation, but less than half a million develop Crohn’s disease.
Published on October 5, 2022 in the review Nature, the new research in mice and human tissues has revealed for the first time that in healthy individuals, immune defenders called T cells secrete a protein called inhibitor of apoptosis 5 (API5), which signals to the immune system to stop the attack on the cells of the intestinal mucosa. This protein adds an extra layer of protection against immune damage, so even people with the mutation can have a healthy gut. However, scientists have also found that norovirus infection blocks API5 secretion from T cells in mice bred to have a rodent form of Crohn’s disease, killing gut lining cells in the process.
Led by scientists at NYU Grossman School of Medicine, the research findings support the theory that API5 protects most people with the mutation from disease until a second trigger, such as a norovirus infection, pushes some to cross the threshold of the disease.
In experiments centered on mice genetically engineered to have the mutation linked to Crohn’s disease in humans, mice injected with API5 survived, while half of the untreated group died. This confirmed the hypothesis that the protein protects intestinal cells, say the study authors. In human tissues, the researchers found that people with Crohn’s disease had between 5 and 10 times fewer API5-producing T cells in their intestinal tissues than those without the disease.
“The results of our investigation help explain why the genetic links to Crohn’s disease are much broader than the actual number of people with the disease.” — Shohei Koide, PhD
“Our findings offer new insight into the key role that apoptosis inhibitor 5 plays in Crohn’s disease,” said Yu Matsuzawa-Ishimoto, MD, PhD, lead study author and gastroenterologist. “This molecule could constitute a new target for the treatment of this chronic autoimmune disease, which has proven difficult to manage in the long term.
According to Dr. Matsuzawa-Ishimoto, a postdoctoral researcher at NYU Langone Health, current therapies, which work by suppressing the immune system, put patients at high risk of infection and often become less effective after a few years of use. A processing method targeting API5, he adds, could avoid these problems.
In another series of experiments, the researchers created organ-like structures from tissue taken from humans who tested positive for the mutation. Notably, these structures consisted only of cells from the intestinal mucosa. Next, the research team deposited API5 in these “mini intestines” and discovered that this treatment protected the cells of the intestinal mucosa. Moreover, the addition of API5-producing T cells also protected the intestinal mucosa.
“Our study suggests that when norovirus infects those with a weakened ability to produce inhibitor of apoptosis 5, it tips the scales toward a full-fledged autoimmune disease.” — Ken H. Cadwell, PhD
“The results of our investigation help explain why the genetic links to Crohn’s disease are much broader than the actual number of people with the disease,” says Shohei Koide, PhD, study co-lead author and biochemist. . Dr. Koide is a professor in the Department of Biochemistry and Molecular Pharmacology and a member of the Perlmutter Cancer Center at NYU Langone.
“Our study suggests that when norovirus infects those whose ability to produce inhibitor of apoptosis 5 is weakened, it tips the scales towards a full-fledged autoimmune disease,” adds the co-lead author of the paper. study and microbiologist Ken H. Cadwell, PhD, Recanati Family Professor of Microbiology at NYU Langone.
Dr Cadwell warns that while the study authors derived the API5 protein from human tissue rather than rodents, it remains unclear whether the injection treatment can be safely administered in humans.
Next, the research team plans to explore the long-term effects of API5 injections to better understand whether the prospective treatment can effectively manage Crohn’s disease, which can flare up repeatedly over a long period.
Reference: “γδ IEL API5 effector masks genetic susceptibility to Paneth cell death” by Yu Matsuzawa-Ishimoto, Xiaomin Yao, Akiko Koide, Beatrix M. Ueberheide, Jordan E. Axelrad, Bernardo S. Reis, Roham Parsa, Jessica A. Neil, Joseph C. Devlin, Eugene Rudensky, M. Zahidunnabi Dewan, Michael Cammer, Richard S. Blumberg, Yi Ding, Kelly V. Ruggles, Daniel Mucida, Shohei Koide, and Ken Cadwell, October 5, 2022, Nature.
Besides Dr. Matsuzawa-Ishimoto, Dr. Koide, and Dr. Cadwell, the other NYU Langone researchers involved in the study were Xiaomin Yao, PhD; Akiko Koide, PhD; Beatrix M. Ueberheide, PhD; Jordan E. Axelrad, MD, MPH; Jessica Neil, Ph.D.; Joseph Devlin, PhD; Eugene Rudensky, PhD; Mr. Zahidunnabi Dewan, PhD; Michael Cammer, PhD; Kelly V. Ruggles, Ph.D.; and Daniel Mucida, PhD. The other researchers in the study were Bernardo Reis, PhD, and Roham Parsa, PhD, of Rockefeller University in New York; Richard Blumberg, PhD, at Harvard Medical School in Boston; and Yi Ding, PhD, at Geisinger Health in Danville, Pennsylvania.
Funding for the study was provided by National Institutes of Health grants R0IL123340, R0IDK093668, R0IAI140754, R0IAI121244, R0IAI130945, R0IDK124336, and R0IDK088199. Additional funding was provided by the Howard Hughes Medical Institute, Kenneth Rainin Foundation, Crohn’s & Colitis Foundation, and Takeda-Columbia-NYU Alliance.
Dr. Cadwell has received research support from Pfizer, Takeda, Pacific Biosciences, Genentech and Abbvie, and has consulted for Puretech Health, which develops microbiome therapies, as well as GentiBio and Synedgen. Dr. Koide has received research support from Argenx BVBA, Black Diamond Therapeutics and Puretech Health, and has been a consultant for Black Diamond Therapeutics. NYU Langone has patents pending (10,722,600, 62/935,035, and 63/157,225) for therapies developed from this therapeutic approach, including Dr. Cadwell, Dr. Koide, Dr. Matsuzawa-Ishimoto, and NYU Langone can benefit financially. The terms and conditions of these relationships are administered in accordance with NYU Langone policies.