Epstein-Barr Virus Linked to Seven Serious Diseases

Top Breakthrough Discovery | Published May 2018 in Nature Genetics

Normally, we think of the transcription factors that regulate human gene expression as being human. But when this virus infects cells, it makes its own transcription factors.

A far-reaching study delving into the disease-triggering influences of transcription factors reports that the Epstein-Barr virus (EBV)—best known for causing mononucleosis—also increases the risks for some people of developing seven other major diseases.

Combined, these diseases—systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), celiac disease, and type 1 diabetes (T1D)—affect nearly 8 million people in the U.S.

The study was led by three members of the Center for Autoimmune Genomics and Etiology (CAGE) at Cincinnati Children’s: John Harley, MD, PhD, Director; Leah Kottyan, PhD, and Matthew Weirauch, PhD. Critical contributions were provided by CAGE members Xiaoting Chen, PhD, and Mario Pujato, PhD.

Breakthrough findings

The study shows that seemingly unrelated disease states actually share a common set of transcription factors (TFs) in addition to the EBNA2 protein from the Epstein-Barr virus. The specific disease risk varies according to where the TF clusters attach along the genome.

“Our study has uncovered potential leads for many other diseases. We cannot possibly follow up on all of these, but we are hoping that other scientists will.”

Harley has devoted much of his career to studying lupus and found possible links to EBV years ago. Scientists also have linked EBV to certain lymphatic cancers and many have suspected a link to MS.

“This discovery is probably fundamental enough that it will spur many other scientists around the world to reconsider this virus,” Harley says. “As a consequence— assuming that others can replicate our findings—that could lead to therapies, ways of prevention, and ways of anticipating disease that do not now exist.”

At a high level, the findings shed new light on how environmental factors from viral infections to pollution exposure can interact with the genome to influence disease risk. In fact, the research team went on to identify over 2,000 similar TF clusters—only a few associated with EBNA2—for 94 conditions, including breast cancer.

“Normally, we think of the transcription factors that regulate human gene expression as being human,” Kottyan says. “But in this case, when this virus infects cells, the virus makes its own transcription factors, and that’s what we suspect is increasing risk for the disease.”

Detecting and tracking the activities of these transcription factors took years of work involving dozens of laboratory and computational experts. The project required gathering massive sets of genetic data, then analyzing every genetic change affecting the activity of the virus. Doing this required creating two new algorithms, called RELI and MARIO. Both software tools and a related website will be made publicly available.

“We are going to great lengths to not only make the computer code available, but all of the data and all of the results,” Weirauch says.

The immediate impact of the study included more than 400 Twitter posts that reached over 600,000 followers and attracted 31,000 video views on Facebook. The study generated more than 80 online news articles; including coverage by U.S. News & World Report, the UK’s Daily Mail, and several Canadian radio stations.

The findings also drew a comment from NIAID Director Anthony Fauci, MD. “Many cases of autoimmune illness are difficult to treat and can result in debilitating symptoms,” Fauci said in a news release. “Studies like this are allowing us to untangle environmental and genetic factors that may cause the body’s immune system to attack its own tissues.”

An image showing intersections between known gene risk loci and transcription factor binding interactions.

Click image to learn more.

Follow-up studies under way

Harley and colleagues have been busy presenting their findings. Settings have included lectures at Harvard, Columbia and other universities; the American College of Rheumatology Annual Meeting in Chicago; the International Conference on EBV and KSHV in Madison, WI; and talks in Austria, Australia, Chile, China, Mexico and Switzerland.

It appears clear that the full impact of this study will take years to explore.

So far, research teams involving several divisions at Cincinnati Children’s are exploring potential TF cluster influences on at least 10 conditions, including inflammatory bowel disease, asthma, MS, RA, lupus, cleft palate, HIV, microangiopathy, renal cell carcinoma and esophageal atresia. Investigators from several other centers also have contacted Harley.

“Our study has uncovered potential leads for many other diseases,” he says. “We cannot possibly follow up on all of these, but we are hoping that other scientists will.”

Motivation to find a vaccine

So far, no vaccine exists that will prevent EBV infection. Developing one remains a major scientific challenge. But now, the scientific community has new incentive to continue the hunt.

“Some EBV vaccines are under development,” Kottyan says. “I think this study might well encourage them to push forward faster and with rededicated effort.”


Harley JB, Chen X, Pujato M, Miller D, Maddox A, Forney C, Magnusen AF, Lynch A, Chetal K, Yukawa M, Barski A, Salomonis N, Kaufman KM, Kottyan LC, Weirauch MT. Transcription factors operate across disease loci, with EBNA2 implicated in autoimmunity. Nature Genetics. 2018 May;50(5):699-707.