SARS-CoV-2 is unusual for the high frequency of long-term complications. But it is quite typical for viral infections to cause rare complications. Epstein-Barr virus infection is a root cause of multiple sclerosis, flaviviruses can cause arthritis, and Coxsackievirus can cause type 1 diabetes, and there are multiple other suggested links that have not been conclusively shown.

One such link is between roseolovirus, a kind of herpesvirus, and autoimmune gastritis, in which the stomach lining becomes inflamed.

Like many possible viral culprits, though, roseolovirus has been hard to convict beyond a reasonable doubt. Like Epstein-Barr virus, whose causal contribution to multiple sclerosis took a study with nearly 10 million subjects to nail down, infection with roseolovirus is near ubiquitous. And like multiple sclerosis, autoimmune gastritis is rare.

In the February 28, 2022, issue of the Journal of Experimental Medicine, researchers from Washington University in St. Louis have demonstrated that in a mouse model, there is a causal link between murine roseolovirus and autoimmune gastritis.

Furthermore, that link occurs via a previously unknown mechanism.

The team showed that "the virus is impacting the thymus, which trains T cells," first author Tarin Bigley told BioWorld Science. "And that disruption results in an escape of autoreactive T cells."

That finding opens up "a different way to think about how a viral infection could induce autoimmunity."

The best-known mechanism of virally induced autoimmunity is molecular mimicry, in which immune cells mistake a self-protein for a similarly shaped viral target.

But there are other potential mechanisms such as what's called the bystander effect. "During an infection and a high amount of inflammation and cell death, cellular proteins can be [attacked by] immune cells that are already activated," Bigley said.

In their work, the team investigated possible mechanisms of autoimmune gastritis by infecting newborn mice with mouse roseolovirus, which will induce autoimmune gastritis once the animals are juveniles. Prompt antiviral treatment prevented the development of autoimmune gastritis, while mice who were treated at 2 months of age went on to develop gastritis, demonstrating that active viral infection was not necessary.

The team also found, to their surprise, that the animals produced not just the autoantibodies leading to gastritis, but a wide variety of autoantibodies.

"That was really the tip that we needed to study something broader," Bigley said. "Early on, we weren't sure if we had to look in the thymus, or in the stomach, or somewhere else" for how the virus was affecting immunity.

That disconnect may be one reason other virus-autoimmunity links have been hard to confirm. "It is very hard to find the culprit... that was never even at the scene of the crime," senior author Wayne Yokoyama, Sam J. Levin and Audrey Loew Levin Professor of Arthritis Research at Washington University of St. Louis, said in a prepared statement.

Going forward, Bigley, who is a fellow in pediatric rheumatology and immunology, plans to set up systems to compare mouse and human roseolovirus.

And beyond insights into the specific relationship between roseolovirus and autoimmune gastritis, the two may serve as a model for gaining new insights into virally induced autoimmunity.

In many cases where an infection causes autoimmunity, there is time lag between the two. Sometimes that lag can last years or decades.

"This potentially gives us a way to try to understand what is happening in that time frame," Bigley said.

The model system may also be able to answer a chicken-and-egg question in viral autoimmunity. "In our rheumatology patients, it is not uncommon to see flares after infections," Bigley noted, leading to the question "Is the virus a trigger of disease itself, or is it the trigger of inflammation in someone who already has autoimmune disease?"