New research may have solved a mystery surrounding Crohn’s disease, a type of inflammatory bowel disease in which immune defenses designed to attack invading microbes accidentally target the body’s own digestive tract instead. Norovirus is a common infection that causes vomiting and diarrhea. It’s also one of several viruses and bacteria thought to trigger disease onset in people with Crohn’s disease, but the field isn’t sure 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 that norovirus disease is called “food poisoning,” “stomach disease,” or “stomach flu.” While noroviruses are the leading cause of foodborne illness, other germs and chemicals can also cause foodborne illness.
One clue emerged when previous studies found that a particular genetic change (mutation) is present in most people with the condition. This genetic mutation makes intestinal wall cells more vulnerable to damage. However, the mystery grew again when it was revealed that half of all Americans have the same risk-causing genetic mutation, but less than half a million develop Crohn’s disease.
Published on October 5, 2022 in the magazine Nature, the new research in mice and human tissue revealed for the first time that in healthy individuals, immune defenders called T cells secrete a protein called apoptosis inhibitor 5 (API5), which signals the immune system to stop attacking gut wall cells. . This protein adds an extra layer of protection against immune damage, so even those with the mutation can have a healthy gut. However, the scientists also found that norovirus infection blocks API5 T-cell secretion in mice bred to have a rodent form of Crohn’s disease, killing the gut lining cells.
Led by scientists at the NYU Grossman School of Medicine, the study results support the theory that API5 protects most people with the mutation from the disease until a second trigger, such as a norovirus infection, pushes some over the disease threshold.
In experiments targeting mice genetically modified to have the mutation linked to Crohn’s disease in humans, mice given an injection of API5 survived, while half of the untreated group died. This confirmed the hypothesis that the protein protects intestinal cells, the study authors say. In human tissue, the researchers found that those with Crohn’s disease had between 5 and 10 times fewer API5-producing T cells in their gut tissue than those without the disease.
“The results of our study help explain why the genetic links to Crohn’s disease are much broader than the actual number of people who have the disease.” — Shohei Koide, PhD
“Our findings provide new insight into the key role that apoptosis inhibitor 5 plays in Crohn’s disease,” said Yu Matsuzawa-Ishimoto, MD, PhD, the study’s lead author and gastroenterologist. “This molecule may represent a new target for the treatment of this chronic autoimmune disease, which has proven difficult to treat 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 treatment approach targeting API5, he adds, could prevent these problems.
In another set of experiments, the researchers created organ-like structures from tissue collected from people who tested positive for the mutation. Notably, these structures were only made of intestinal cells. Next, the research team dropped API5 into these “mini-guts” and found that this treatment protected the intestinal wall cells. In addition, adding API5-producing T cells also protected the gut wall.
“Our study suggests that when norovirus infects humans with a weakened ability to produce apoptosis inhibitor 5, it tips the balance into a full-fledged autoimmune disease.” — Ken H. Cadwell, PhD
“The results of our study help explain why the genetic links to Crohn’s disease are much broader than the actual number of people who have the disease,” said Shohei Koide, PhD, co-senior author of the study and a 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 humans with a weakened ability to produce apoptosis inhibitor 5, it tips the balance into a full-fledged autoimmune disease,” adds co-senior author and microbiologist Ken H. Cadwell, PhD, of the Recanati Family. . Professor of microbiology at NYU Langone.
dr. Cadwell cautions that although the study authors derived 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 future treatment can effectively control Crohn’s disease, which can flare up repeatedly over a long period of time.
Reference: “The γδ IEL effector API5 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.
In addition to Dr. Matsuzawa-Ishimoto, Dr. Koide and Dr. Cadwell, 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, PhD; Joseph Devlin, PhD; Eugene Rudensky, PhD; M. Zahidunnabi Dewan, PhD; Michael Cammer, PhD; Kelly V. Ruggles, PhD; and Daniel Mucida, PhD. Other research researchers included Bernardo Reis, PhD, and Roham Parsa, PhD, at Rockefeller University in New York City; Richard Blumberg, PhD, at Harvard Medical School in Boston; and Yi Ding, PhD, at Geisinger Health in Danville, Pennsylvania.
The study was funded by National Institutes of Health grants R0IL123340, R0IDK093668, R0IAI140754, R0IAI121244, R0IAI130945, R0IDK124336, and R0IDK088199. Further funding was provided by the Howard Hughes Medical Institute, the Kenneth Rainin Foundation, the Crohn’s & Colitis Foundation and the Takeda-Columbia-NYU Alliance.
dr. Cadwell has received research support from Pfizer, Takeda, Pacific Biosciences, Genentech and Abbvie, and has served as an advisor to 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 served as a consultant to Black Diamond Therapeutics. NYU Langone has patents pending (10,722,200, 62/935,035, and 63/157,225) for therapies developed based on this treatment approach, of which Dr. Cadwell, Dr. Koide, Dr. Matsuzawa-Ishimoto and NYU Langone can benefit financially. The terms of these relationships are managed in accordance with NYU Langone policies.