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The Strange Connection Between Mono and M.S.

New research proves a virus — one that almost all of us have — “causes” multiple sclerosis.

Denis Burkitt, an Irish surgeon, traveled to Africa during World War II as a member of the Royal Army Medical Corps, and afterward he settled in Uganda to practice medicine. There he observed that a surprising number of children developed strange jaw tumors, a cancer that would come to be known as Burkitt lymphoma. Eventually, Burkitt sent samples of the tumor cells to Middlesex Hospital Medical School in London, where Michael Anthony Epstein, a pathologist, and his colleagues Yvonne Barr and Bert Achong examined them through an electron microscope.

Their findings — they noticed particles shaped like a herpesvirus, only smaller — were published in a landmark paper in The Lancet in 1964 and spurred the realization that this newly identified member of the Herpesviridae family, subsequently named Epstein-Barr virus, was a cause of Burkitt lymphoma. It was the first evidence that a viral infection could lead to cancer. The virus has since been shown to increase the risk of Hodgkin lymphoma, as well as nasopharyngeal and stomach cancer. It is also the virus most often responsible for infectious mononucleosis, a disease usually characterized by extreme fatigue, sore throat, fever and swollen lymph nodes in the neck. These symptoms can last for weeks and, in chronic cases, recur for years.

We now know that upward of 90 percent of adults have the Epstein-Barr virus. As happens with other herpesviruses, once you have been infected, the virus stays with you forever — it deposits its DNA alongside yours in the nucleus of many of your cells. (RNA viruses, like SARS-CoV-2, can be cleared from your body.) Most people contract Epstein-Barr in childhood: It is spread through body fluids, usually saliva; kissing is a frequent route of transmission (as may be the sharing of utensils). Young children, if they get sick at all, typically develop symptoms indistinguishable from those of a cold or flu; mono is more common when the first infection happens after puberty. “Most people never know they’re infected,” says Jeffrey Cohen, the chief of the Laboratory of Infectious Diseases at the National Institute of Allergy and Infectious Diseases.

The virus enters cells at the back of the throat and from there moves into B cells, a type of white blood cell that produces antibodies. In some B cells, the virus replicates, making proteins that the immune system can recognize and subdue. In other cells, though, it remains dormant. “It’s very stealthy,” Cohen says. Ultimately, as those infected B cells circulate throughout the body, they reach the back of the throat again. The virus awakens and starts producing proteins, which its host sheds, potentially spreading the pathogen to others, probably for several days each month. “The vast majority of people who are infected are passing it around,” Cohen says. “It’s shed in our saliva the rest of our lives.”

Scientists have long hypothesized that viruses, including Epstein-Barr, are involved in the development of autoimmune diseases, in which the immune system mistakenly attacks healthy tissue. Evidence links it to lupus, and a recent study reported that people with long Covid were more likely than others to have an active Epstein-Barr infection (though it is unclear whether that infection causes symptoms, because the virus can proliferate when the immune system is under stress without creating any health problems). There are documented associations between mono and multiple sclerosis, a disease in which the immune system destroys a protective sheath called myelin that coats nerve fibers, often disabling communication between the nervous system and the rest of the body. “People have been trying for many, many decades to prove that a virus causes M.S. or rheumatoid arthritis,” says William H. Robinson, the chief of the immunology and rheumatology division at Stanford. “And they have not been able to convincingly demonstrate that it does.”

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Credit…Illustration by Andrea Ucini

The very ubiquity of Epstein-Barr has made it especially difficult to isolate as a causal factor. To show that Epstein-Barr causes M.S., or any other condition that takes years to develop, researchers would need to find a group of people who don’t have the virus and follow them over decades to see who becomes infected — and of those, how many go on to develop M.S., compared with how many without Epstein-Barr do. Such a study would need tens of thousands of participants, because only about 10 percent of the adult population has not been infected by Epstein-Barr by their mid-20s, and an even smaller number of people — 1 in 330 in the U.S. — develop M.S., usually between age 20 and 50.

Researchers from the Harvard T.H. Chan School of Public Health and elsewhere, however, devised a novel way to carry out that study, and they published their findings in January in Science. U.S. military recruits, a group of more than 10 million people, are screened for H.I.V. when their service starts and biennially thereafter. Their blood serum samples are then archived in the Department of Defense Serum Repository and can be retested for other pathogens. Between 1993 and 2013, the researchers identified cases of M.S. among active-duty U.S. military personnel. Then they tested their first serum sample; their last sample before M.S. onset; and one in between. They found that of 801 soldiers with M.S., 800 were positive for Epstein-Barr.

They also looked at serum samples from a randomly selected group of those participants’ peers with similar characteristics, such as age, gender, race and branch of service. At the time of the first sample, 35 of the M.S. cases tested negative for the virus and 107 of the controls did. By the last test, all but one of the M.S. cases were positive for the virus, whereas only 57 percent of those who didn’t have M.S. were. “In practical terms, if you’re not infected with E.B.V., your risk of M.S. is virtually zero,” says Alberto Ascherio, a professor of epidemiology and nutrition at Harvard and a senior author of the Science study. “After infection, your risk jumps by over 30-fold.” The odds of that increase having occurred by chance are less than one in a million.

That was the strongest evidence yet that Epstein-Barr initiates M.S., but it didn’t explain why. Just over a week after the Science paper came out, though, Robinson and colleagues published their own paper in Nature that demonstrated how the virus triggers the disease in some people. Epstein-Barr produces proteins that mimic a protein in the myelin sheath, they found; when the immune system makes antibodies to attack the virus, they also attack the myelin — “the insulation around your neurons,” as Robinson puts it. “Like electrical wires, if the insulation gets stripped off, it short-circuits,” he says. “That’s what results in M.S.”

This protein mix-up, though, can only explain about a quarter of M.S. cases. And while the Science paper concludes that Epstein-Barr is the “leading cause” of M.S., Cohen says he wants to be careful with the word “cause.” He thinks the study proves that the virus is a necessary precondition for M.S., but the fact that so many people have Epstein-Barr and so few of them get M.S. demonstrates that other factors, very likely including genetic susceptibility, must play a significant role in the development of the disease. Still, similar hard-to-disentangle circumstances describe other diseases for which most people do feel comfortable pointing to a specific culprit. The C.D.C. refers to polio as “a disabling and life-threatening disease caused by the poliovirus,” for instance, but fewer than five in a thousand people who contract the virus develop serious symptoms.

What is exciting about the discovery that Epstein-Barr is necessary for M.S. is that it raises the prospect that a vaccine could prevent that disease — as well as other serious conditions — even if we never understand precisely why the virus behaves as it does in a given individual. As long as the link between Epstein-Barr and M.S. remained controversial, commercial and popular interest in such a vaccine was “lukewarm,” says Hank Balfour, a professor of laboratory medicine, pathology and pediatrics at the University of Minnesota Medical School and the principal investigator of the Mono Project, an Epstein-Barr disease research group that hopes to begin clinical trials of a vaccine this year. “Now I think things will change.”

Kim Tingley is a contributing writer for the magazine.

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