Gut punch: New study knocks out norovirus where it strikes | Yale News

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Listen to this story<br>Gut punch: New study knocks out norovirus where it strikes

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As the leading cause of viral gastroenteritis worldwide, norovirus is an all too familiar ailment. Its telltale digestive upset — not to mention its reputation for being notoriously contagious — has earned it the nicknames “winter vomiting bug” and “stomach flu.”

What you need to know

Why is it important to develop effective norovirus treatments?<br>While most healthy people recover completely in a few days, norovirus does pose serious risks. The World Health Organization estimates that there are 685 million cases worldwide annually, including 200 million cases among children under five. Norovirus causes up to 200,000 deaths per year, including 50,000 child deaths, primarily in low-income countries.

What are the best ways to prevent norovirus infection?<br>Norovirus is highly transmissible, spreading via contact with infected individuals, and contaminated food or water. The virus can also live on objects like doorknobs, countertops, and phones for days or weeks. To prevent norovirus infection, experts encourage people to avoid sick individuals, wash their hands with soap often (especially after using the bathroom and before eating), wash fruits and vegetables thoroughly, and immediately disinfect areas or clothing that encounter contaminated bodily fluids.

Why are there no effective drugs or vaccines for norovirus?<br>The development of drugs or vaccines for norovirus has been slowed by limited understanding of the biology and the immunology of the infection. In new research, Yale researchers show that future efforts should focus on developing immunity in the gut rather than creating antibodies that circulate in the blood.

Yet despite millions of dollars spent on research, there are still no vaccines or anti-viral drugs for norovirus.<br>A new Yale study, however, offers an important clue into where future treatments might be found: To beat the stomach flu, the researchers found, one should take the fight to the gut.<br>The findings, published in the journal Science Translational Medicine, upend traditional vaccine development efforts which to date have focused on creating norovirus-fighting antibodies that circulate in the blood rather than taking up residence in the gut.<br>According to findings, mucosal IgA (Immunoglobulin A) antibodies — which are found primarily in the body’s mucosal surfaces, including the lungs, airway, the intestines, and gut — provide key immune defense against norovirus.<br>Therefore, the researchers say, the path to norovirus vaccines should focus on generating IgA, gut-based immunity.<br>“One of the big challenges with norovirus is there are no drugs or vaccines, but that’s not simply due to lack of investment. It’s due to our limited understanding about the biology and the immunology of norovirus infection,” said study senior author Craig Wilen, an associate professor of laboratory medicine and immunobiology at Yale School of Medicine (YSM).<br>“By using mouse models, we discovered that IgA was both necessary and sufficient for protection against norovirus.”

Co-senior author Craig Wilen and first author Arya Okten

Photo courtesy of Yale School of Medicine

This study was led by first author Arya Ökten, who recently defended her Ph.D. in the labs of Wilen and of Joseph Craft, the Paul B. Beeson Professor of Medicine (Rheumatology) and Professor of Immunobiology at YSM.

This discovery opens the door to potential norovirus treatment strategies that use mRNA technology to deliver protective antibodies directly into the gut.

For the study, the researchers first measured immune responses in cases of norovirus infection. They found that immunoglobin G (IgG) — the most common antibody in the blood which fights infections throughout the body — appeared quickly. Gut IgA, meanwhile, developed much more slowly.<br>Then, using genetically engineered mice, they discovered that B cells (which are immune cells that produce antibodies) and IgA were essential in fighting norovirus, while CD8 T cells (specialized immune cells that identify and destroy infected cells) were not.<br>They then examined reinfection with norovirus and found that mice with prior infection were largely protected, but engineered mice lacking IgA lost protection. Seeking a way to capitalize on IgA-mediated immunity, the researchers collaborated with Ted Kreider, assistant professor of medicine at the University of Pennsylvania. Together, they engineered mRNA lipid nanoparticles to produce anti-norovirus IgA.<br>This, they found, completely protected the mice from norovirus infection.<br>This discovery opens the door to potential norovirus treatment strategies that use mRNA technology to deliver protective IgA...