A growing body of research suggests that viral DNA or proteins introduced into the body can contribute toward the development of serious diseases long after the initial viral infection has passed.
Now, a groundbreaking study by a team from the Cincinnati Children’s Hospital shows that exposure to the Epstein-Barr virus (EBV), best known for causing mononucleosis, appears to boost the risk of developing seven other diseases in individuals who inherited predisposing gene variants. Those autoimmune diseases are lupus, multiple sclerosis, rheumatoid arthritis, juvenile idiopathic arthritis, inflammatory bowel disease, celiac disease, and type 1 diabetes.
The paper, published in Nature Genetics, sheds light on how diseases with complex origins may arise and provides molecular targets for future treatments.
EBV is so prevalent that an estimated 90 percent of individuals will be infected by the time they are 20. Once inside the body, the virus inserts a copy of its genome into B cells, instructing the cell to produce its viral proteins for it. When the B cell replicates and divides, so does the viral genome, and thus, the virus and its protein products linger in the body indefinitely.
The seven diseases are known to arise after B cells mistakenly flag the body’s own tissue as dangerous, yet a combination of environmental and genetic factors appear to be at play.
To connect the dots between EBV, B cells, genetics, and the development of autoimmune disease, Harley’s team analyzed a large database of DNA sequences from EBV-infected and EBV-negative B cells using an algorithm that identifies regions where proteins that may influence gene transcription are bound to the strand.
As they had suspected, an EBV protein called ENBA2 appears to consistently attach itself to human DNA near lupus risk sequences. And when ENBA2 is present, transcription factors – proteins made by the cell that influence gene expression – also bind near the gene, thereby increasing the likelihood that a lupus-associated gene will be activated.
Repeating the experiment for other regions of the genome revealed that ENBA2, and the associated human transcription factors, will also bind to sequences associated with risk for the other six autoimmune diseases.
Altogether, the findings suggest that EBV-derived proteins are a trigger for “switching on” disease-causing genetic mutations in B-cells that may have otherwise never been expressed.
Using their algorithm, the authors then identified specific associations between risk sequences for 94 other diseases, including breast cancer, and known transcription factors.
Other scientists may now use this data to develop new disease treatments. In regards to the seven autoimmune conditions, the authors note that a recently described protein can inhibit ENBA2.
“This discovery is probably fundamental enough that it will spur many other scientists around the world to reconsider this virus in these disorders,” Harley said in a statement. “As a consequence, and assuming that others can replicate our findings, that could lead to therapies, ways of prevention, and ways of anticipating disease that don’t now exist.”
“I’ve been a co-author in almost 500 papers. This one is more important than all of the rest put together. It is a capstone to a career in medical research.”