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Roseoloviruses, which commonly infect humans, have been proposed to cause a range of autoimmune diseases, but how they might do this has yet to be nailed down. Now, a study shows that in mice, infection with a roseolovirus leads to the development of autoimmune gastritis later in life, demonstrating a causal link between roseolovirus infection and autoimmunity. The results appeared February 28 in the Journal of Experimental Medicine.
Nearly everyone has been infected at some point with the human roseoloviruses HHV-6 and HHV-7. The resulting illness is usually a childhood infection that is characterized by a few days of high fever followed by a rash, but the virus sticks around in the body after those acute symptoms resolve. Previous research has suggested that roseolovirus infection plays a role in autoimmune diseases, and more recent studies suggest human roseolovirus may be a trigger for the severe autoimmune disorder systemic sclerosis. However, few animal models have been available to try to tease out possible mechanisms for that particular link.
A research group led by Wayne Yokoyama, a rheumatologist at Washington University School of Medicine, St. Louis, had previously identified and sequenced a mouse version of roseolovirus called murine roseolovirus (MRV), which is highly related to human roseoloviruses. Curiously, the symptoms of MRV infection resemble those of mouse thymic virus (also called mouse thymic lymphotropic virus), but the researchers couldn’t definitively determine whether they’re one and the same because no samples tracing back to the original description of mouse thymic virus are publicly available. “This last paper published on [mouse thymic virus] showed neonatal infection resulted in the development of autoimmune gastritis later in life,” Tarin Bigley, a rheumatologist at Washington University School of Medicine, St. Louis, and coauthor of the new study, tells The Scientist. “As a potentially similar virus induces autoimmunity later in life, this sparked the interest for this paper” looking at the effects of roseolovirus infection.
In the current study, Yokoyama, Bigley, and their colleagues observed that neonatal mice infected with murine roseolovirus develop autoimmune gastritis—that is, inflammation of the stomach—later in life, at week 12. It wasn’t just infection, but particularly viral replication that led to gastritis: when the researchers blocked viral replication in the first week of life—but not initial entry or viral gene expression—the infection alone did not induce autoimmune gastritis. “What was also surprising to us is that when we looked for virus replication in the stomach, where we were seeing autoimmune disease, we didn’t see viral replication,” Bigley says. Instead, inflammation in the stomach occurred weeks to months after the acute viral infection had resolved. “This suggested that there might be something broader, in terms of loss of tolerance and development of autoimmune disease.”
Two well-explored explanations for autoimmunity after viral infection are molecular mimicry and the bystander effect. In molecular mimicry, similarities between a viral protein and a cellular protein result in immune cells mistakenly attacking the body, while in the bystander effect, the high level of inflammation induced by viral infection activates immune cells and leads them to attack healthy tissue. Neither mechanism is likely at work here, says Bigley: The broad autoantibody response observed after roseolovirus infection argues against mimicry, where a cellular protein is recognized by chance. “As far as the bystander effect is concerned, we weren’t seeing inflammation of the stomach during infection, and we didn’t see replication in the stomach. So it didn’t really fit that the virus was causing so much inflammation in the stomach that immune cells would become dysregulated and recognize stomach cells.”
In addition, it turned out to be more than the stomach that was under attack. “We saw auto-antibodies to a wide range of other targets, which suggested to us that there might be a broader auto-immune response that’s occurring after neonatal infection,” Bigley says. The researchers therefore focused on the thymus, the organ in which T cells are trained not to go after the body’s own cells. They found that some of the mechanism of this central tolerance appeared to be disrupted by roseolovirus infection, resulting in the release of autoreactive T cells that then attacked the stomach.
This “solid” study shows “a new mechanism that can explain how a virus infection can trigger autoimmunity, in addition to well-known mechanisms such as antigenic mimicry, epitope spreading, or bystander effect,” Jean-Paul Coutelier, who researches infectious diseases and immune regulation at the Catholic University of Louvain in Belgium and was not involved in the study, tells The Scientist in an email.
Matthias von Herrath, a researcher in autoimmune diseases at the La Jolla Institute for Immunology who was not involved in the study, calls the study’s finding of a roseolovirus-gastritis link “an interesting observation.”
“As far as I know there are no known viral associations of human Roseola-virus (HHV6) and autoimmune gastritis, but if this is a hit-and-run effect where changes only manifest much later, it is of course epidemiologically hard to establish,” he tells The Scientist in an email. “In addition to disruption of thymic tolerance there can also be other mechanisms in place—one other matter that likely camouflages such associations in humans is that viruses can also prevent autoimmunity under certain circumstances.”
The researchers are further investigating how exactly roseolovirus infection disrupts central tolerance. “We are trying to figure out whether it has to do specifically with the pathways that the virus alters during infection, or potentially the inflammatory response to the virus in the thymus that then impacts tolerance. Either of those are possible,” Bigley explains. The team is also investigating how auto-antibodies to nonstomach targets may translate to autoimmune disease of other organs.
The mouse model offers some clues to what might be going on in human roseolovirus infections that precede autoimmunity, says Bigley. One important finding, he says, is that replication had to happen during a critical time period for autoimmune gastritis to occur. “The majority of wild mice are infected with this virus, very similar to the majority of humans that are infected at a young age with roseolovirus. We know that the majority of people that are infected with this virus . . . don’t develop autoimmune disease. Our study suggests that potentially the timing of infection or even the background in which infection occurs might be very important for the development of autoimmunity later in life.”