The Italian epidemiologist Alberto Ascherio has solved this year one of the great mysteries of medicine. In January, his team showed that the Epstein-Barr virus, the culprit behind kissing disease, is also “the main cause” of multiple sclerosis, an enigmatic disorder in which the envelope of neurons is destroyed, as if stripping the electrical wires from the brain and spinal cord. Patients, usually diagnosed in their twenties or thirties, can worsen in some cases to difficulty speaking and walking. Until now, the three million people living with multiple sclerosis in the world did not know what the real trigger of their disease was.
In 2000, Ascherio’s team, from Harvard University (USA), began a patient follow-up of some 10 million US soldiers. Their expected results have shown that the risk of multiple sclerosis is multiplied by 32 after infection by the kissing disease virus. Ascherio, 68, from Genoa, speaks perfect Spanish learned in the jungles of Nicaragua after the Sandinista revolution, where he went in 1980 as a volunteer doctor. Before giving a talk at the summer courses at the Menéndez Pelayo International University in Santander, the epidemiologist explains how it is possible that a virus as omnipresent as Epstein-Barr, which infects 94% of citizens, is to blame of a disease as rare as multiple sclerosis, with just 36 cases per 100,000 people.
Ask. If you are not infected with the Epstein-Barr virus, what is your risk of having multiple sclerosis?
Response. Virtually zero. Multiple sclerosis probably does not develop if a person is not infected with the virus.
Q. You have claimed that the virus is “the main cause” of multiple sclerosis. Virologist Jeffrey Cohen, from the US National Institutes of Health, has stated that he prefers to be careful with the word “cause” and speaks of “necessary precondition”. What do you think?
R. The truth is that I do not think so. It is a bit paradoxical, because saying that it is a necessary factor implies that it is a causal factor in 100% of cases. When I say that it is a cause, I say that it is the causal factor of 99.9%, a little less.
Q. You do believe then that the Epstein-Barr virus causes multiple sclerosis.
A. Yes, I think there is no doubt that multiple sclerosis is a rare complication of Epstein-Barr virus infection, but there are always other factors. How is it possible for such a common virus to cause such a rare disease? Well, this is not an exception, it is the rule. The Epstein-Barr virus causes Burkitt’s lymphoma, which is a rare lymphoma, and it also causes nasopharyngeal carcinoma, which is also very rare. Many viruses rarely cause serious illness.
Q. For example?
A. The polio virus, for example, infected almost all children before there was a vaccine. And one in 400 children had paralytic polio, but the other 399 did not. There is always a genetic predisposition, environmental factors, other infections or a set of factors. It is the same thing that happens with covid: some people die and others have no symptoms.
There is no doubt that multiple sclerosis is a rare complication of Epstein-Barr virus infection.
Q. Could there be another cause of multiple sclerosis other than the Epstein-Barr virus? Is there another candidate?
A. No, in our study we investigated all known viruses and no other emerged as a possible candidate. In multiple sclerosis, the virus triggers a complex inflammatory autoimmune process. It is possible, in very rare situations, that this process develops without knowing the cause or that we cannot exclude the option of another virus. But they would be very rare cases.
Q. Almost everyone has the Epstein-Barr virus in their saliva.
A. Yes, it reactivates periodically. If we stop people on the street and test them, 20% will test positive at that time. But you can test negative now and, in two weeks, test positive. Virus excretion is intermittent.
Q. Epstein-Barr virus is like other members of the herpesvirus family: it can integrate its DNA into your own DNA, inside human cells.
A. It can be integrated into human DNA, but in most people the DNA of the virus remains in a small ball inside the human cell. It connects to human DNA when the cell reproduces. As the human cell divides in two, the virus also reproduces.
P. Is it then possible to imagine a treatment that eliminates the virus from our cells?
R. In theory, yes. What can be done is to block the replication of the virus when the cell reproduces.
Q. Do you believe that if the virus is eliminated from a person with multiple sclerosis, it is possible that they will be cured?
R. That is what is not known, honestly. We have shown that the virus causes the disease, but there are two aspects: it can only cause the onset of the disease or it can also cause its progression. It is almost certain that if the virus is present it will continue to stimulate this autoimmune response. It is likely, but it is not certain. It is also possible that, even if the virus is eliminated, this immune process continues on its own. We still don’t know the answer.
Q. It would be unbelievable that it works.
R. It would be incredible and I think it is something that needs to be studied. The only way to know, in my opinion, is to try antiviral treatments. There are some ongoing studies, such as a trial being done with immune cells that kill the virus, cytotoxic T cells specific for Epstein-Barr virus. We ourselves try to carry out studies with an antiviral that is effective against the virus, but we do not have a magic bullet, a drug that definitively kills the virus. There are drugs with intermediate activity, which reduce proliferation, but we do not know if it will be enough.
We do not have a magic bullet, a drug that kills the virus definitively
Q. Have your latest results boosted research into the disease?
R. Yes, I think a lot, at all levels and, especially, in terms of vaccines, because that would be the most logical way to act. If multiple sclerosis is caused by a very aggressive immune response against the virus, a vaccine could modulate that response so that it is less aggressive. The American company Moderna now has an experimental vaccine against the Epstein-Barr virus.
Q. Do we fully understand how the virus behaves in a person with multiple sclerosis?
A. Not really, we still don’t quite understand it. There was a series of investigations in 2007 that showed that in multiple sclerosis lesions there are cells infected with the virus, that the virus reactivates, that the immune system attacks these cells and that causes all the inflammation around it and damages the myelin [la envoltura de las neuronas]. The results seemed very compelling, but later other laboratories were unable to reproduce those results. And others more recently have. They are difficult studies, in which they are working with autopsy material from people who died of multiple sclerosis. It’s a disease that lasts for decades, so we’re trying to understand how the inflammatory process started by looking 10 years later. Is not easy.
Q. What other viruses are implicated in the development of autoimmune diseases?
R. The truth is that there is no very clear evidence. The Epstein-Barr virus itself is probably associated with an increased risk of systemic lupus erythematosus, but most autoimmune diseases are considered to be of unknown cause. Infections likely play a role, but this has not been clearly demonstrated.
Q. The risk of multiple sclerosis in smokers is twice that of non-smokers. Why?
A. The mechanisms are not clear. It is possible that lung inflammation may have some interaction with the Epstein-Barr virus.
Q. And what about the other risk factors for multiple sclerosis, such as childhood obesity?
A. Of the factors that can be corrected, probably the most important factor is vitamin D deficiency. The second would be smoking. Childhood obesity is associated with vitamin D deficiency. Some people believe that there is an effect of obesity independent of the effect of vitamin D, but I’m not 100% sure.
In Parkinson’s, the main conclusion is that physical activity has a protective effect
P. In your laboratory you also study the role of drugs, diet and lifestyle in the risk of Parkinson’s. Do you already have a conclusion?
A. In Parkinson’s, the main conclusion is that physical activity has a protective effect. Regarding diet, we have interesting results, but with a level of certainty that is not as strong. The Mediterranean diet and flavonoids, which are antioxidant components, are associated with a reduced risk of Parkinson’s. Proving causality is complex. We are studying the initial phase of Parkinson’s and we see that the Mediterranean diet is associated with a lower frequency of these first symptoms. We are not talking about preventing 90% of cases with the Mediterranean diet, we are talking about preventing between 10% and 15%. It is promising, because it is the best thing we have after physical activity, but we are not going to eliminate Parkinson’s with diet. But we can eliminate multiple sclerosis with a vaccine.
Q. What is the main hypothesis about the cause of Parkinson’s?
A. There are risk factors, for example, exposure to pesticides. I think it almost certainly increases the risk of Parkinson’s, but we’re talking about doubling the risk. The vast majority of people with Parkinson’s do not have substantial exposure to pesticides. I believe the causes are very complex, with many contributing factors. There are 10% or 15% of cases that have genetic mutations. In the rest of the cases it is not known.
Q. Men have a 1.5 times greater risk than women of having Parkinson’s. Why this can be?
A. Yes, it is more common in men and it is not known why. Differences in disease risk between men and women are common. Multiple sclerosis is more common in women. In most cases it is not known. There is talk of hormones, of course, but it is not really understood.
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