Tiempo de lectura: 10 minutos

No, the image above is not SARS-CoV-2. It is the Epstein-Barr virus, one of the eight within the herpesviruses family that can commonly infect humans. Throughout this past week this virus has managed to steal some of the spotlight from the coronavirus due to a 20-year long study conducted in the Harvard T. H. Chan School of Public Health. A group of researchers at said institution indicated a possible link between Epstein-Barr virus and multiple sclerosis, making it a new intriguing area of research for possible treatments against MS.

But how common is this virus to begin with? And how is it related to multiple sclerosis, a disease of the central nervous system? In today’s article, I will explain key features of the Epstein-Barr virus and summarise the findings linking it to this chronic disease.

What is the Epstein-Barr virus?

The Epstein-Barr virus belongs to the family of herpesviruses, and is commonly known as «the kissing disease» because it is transmitted mainly through saliva. Sharing utensils, cups or toothbrushes are all potential ways of getting infected.

There are over 100 known herpesviruses, but as was mentioned in the introduction, only eight typically infect humans. These are: herpes simplex virus types 1 and 2, varicella-zoster virus, cytomegalovirus, human herpesvirus 6 and 7, Kaposi’s sarcoma virus and Epstein-Barr virus. The members of this family share common traits, such as the synthesis of unique enzymes and the provocation of cell death to release their progeny. The most important feature of herpesviruses though, is that they can remain latent in tissues of the body, dependant on the type of virus. This means that we may be living with these viruses long after symptom onset and treatment.

EBV replicates in the pharynx and in B-lymphocytes. Precisely because of this fact, Epstein-Barr virus has long been hypothesised to be involved in MS.

Structure of Epstein-Barr virus

All herpesviruses contain a large double-stranded DNA. The capsid, which contains the genetic material, is icosahedral and protected by a protein coat called the tegument (see diagram below). This layer is concealed by the viral envelope made up of a lipid bilayer encrusted with glycoproteins.

A surprising feature of the virus is its genome’s subdivisions. These are clearly marked by terminal reiterations, which split the DNA into several parts.

Symptoms of Epstein-Barr virus

The Epstein-Barr virus causes mononucleosis, whose symptoms usually include fatigue, fever, swollen lymph nodes, enlarged spleen, swollen liver, inflamed throat and rash.

Because of how similar these symptoms are to other colds, diagnosing EBV presence will mostly depend on blood tests to find the presence of antibodies for the virus. As you will see, this point is critical to understand the study.

A short history of isolating Epstein-Barr virus

This section is completely voluntary and not needed to understand the connection between EBV and MS. However, the history of how EBV was first isolated contains interesting points on the nature of science, including perseverance and luck. If you are interested, keep on reading! Otherwise, skip over to learn about MS.

How was Epstein-Barr discovered?

In 1964, a strike of serendipity led Michael Anthony Epstein and Yvonne Barr to the isolation of this virus, formerly known as Human Herpesvirus 4 from a Burkitt’s lymphoma sample.

Epstein’s interest in this virus began with his fascination of a rare and fatal tumor that affected African children in specific geographical locations (later named after the doctor who discovered it: Burkitt’s lymphoma). He believed the onset of this tumor had to do with an insect vector which transmitted a cancer-causing virus. That’s right, certain viruses can cause cancer too. For example, Rous sarcoma virus, Epstein’s main research area at the time, was the first to be described is also an oncovirus. Because of his work, he thought that Burkitt’s lymphoma might also be caused by an oncovirus. However, when it came time to cultivate and grow the cells from samples he had shipped to the UK from Uganda to study the virus, he was unsuccessful.

Growing the cells

In order to isolate the virus, Epstein first had to grow the cells from the samples he had shipped to the UK from Uganda. However, none of his methods were working.

It was not until he hired two other scientists, Bert Achong and Yvonne Barr, that luck struck. One of the samples was sent to Manchester during an intense storm, extending its time on the plane. When it finally arrived to Epstein, the lymphoma was in a murky liquid. After analysing this substance under the microscope, the researchers determined that what was causing that appearance was a tumor cell suspension, which could then be used to study and isolate the virus. This method had large implications on how tumor cells were cultivated and is still standard practice nowadays.

Once they were able to grow the cells, they began to look for the virus. By using an electron microscope, Epstein was able to observe a herpes like virus in the cells, which did not behave like any known member of this family. After this discovery, the virus was coined as the Epstein-Barr virus.

What is multiple sclerosis?

Multiple sclerosis (MS) is a disease of the central nervous system caused by the breakdown of the myelin sheath which surrounds neurons. The myelin sheath is formed thanks to Schwann cells, which also aid in the conductivity of electrical impulses, by allowing the signal to jump from one node to the next (nodes of Ranvier). In this way, the transmission of nervous impulses much faster than if the axon were bare.

Common symptoms of MS include fatigue, difficulty walking, speech impediments and vision problems. However, each person may differ both in the symptoms and in the severity with which they experience them. Oftentimes, these will come in bursts of episodes followed by periods of remission. Depending on whether the symptoms worsen over time or become continuous, the disease can be classified in one of several ways, affecting the treatments given. Multiple sclerosis is not fatal on its own, but can cause other problems which may shorten the lifespan. Unfortunately, there is still no definitive cure.

Therefore, researchers have long been set out to find what causes this breakdown of myelin to find possible therapies. Many attributed the process of demyelation to an immune system attack, and finally it seems that there may be a clearer answer.

The study

The study, published in January 2022, has established a causal link between infection of EBV and MS. Researchers had struggled to identify which way the relationship went in. Did MS cause EBV infection or did EBV cause MS? Thanks to this paper, which included data collected over 20 years, there is now some clarity in the matter.

The beauty of the study

In science, it is typically challenging to say «A causes B.» In fact, most scientific articles will be flooded with caveats to prevent readers from making these relations and spreading false information. In order to truly accept that there is a causal relation, all other variables must have been controlled and proven not to have an influence over the end result or conclusion. Because of the complexity of human biology, epigenetics, genetic variability, race, gender, age, etc. it is near impossible to isolate a single consequence (development of MS) to a single cause (prior EBV infection). Yet, this study was able to do so, which is where its true beauty and elegance lie.

The scientists used data from the US military gathered between 1993 and 2013. This may sound like a strange cohort to base this study on, but think about the diversity of this population and amount of information available. Over 10 million individuals were part of the research, spanning a racially diverse population, including both men and women, across different age ranges. Furthermore, the time stamping of each sample allowed the researchers to easily monitor the parameters of the study.

Determining causality

According to the CDC, over 95% of adults will have had EBV at some point in their lifetime. This makes it one of the most common viruses that affect the human population. Meanwhile, MS is a relatively rare disease affecting only 2.5 million people in the world (the world’s population is currently close to 8 billion). Therefore, studying the causality between EBV and MS is difficult and has required such a large sample size.

The paper states that «causality implies that some individuals who developed MS after EBV infection would not have developed MS if they had not been infected with EBV.» To prove this, they matched each MS case that they found (801) to two other individuals who did not suffer MS with the same physical characteristics. Then, they compared the blood samples of the positives and the controls from the same dates.

Through this methodology, they found that developing MS in EBV seropositive individuals (containing anti-EBV antibodies) was 32.4 times more likely than developing MS in EBV seronegative individuals.

What about other factors?

To rule out possible environmental factors influencing these results, the researchers also tested for cytomegaolvirus (CMV), a member of the herpesvirus which is also transmitted through saliva. As was hypothesised, CMV did not increase the risk of developing MS, rather it decreased it. This had already been suggested in previous reports, so it was not a new finding (apparently, CMV counteracts the effects of EBV).

Additionally, they investigated other factors, such as a specific biomarker of MS and the presence of other viruses in the serum, but the results of these experiments continued supporting their hypothesis.

Remaining questions

While this paper is quite thorough and careful in establishing the causal relationship between EBV and MS, other questions still remain. For example, what exactly does EBV do to trigger MS? Can EBV be targeted directly to treat MS? Will there be an EBV vaccine in the future to prevent MS? Moreover, EBV was found to be necessary for MS, but it is not sufficient. Otherwise, 95% of the population would suffer from MS. Fortunately this is not the case, but what then, combined with EBV, complete the recipe for the chronic disease?

Due to how recent this study is, we still don’t know how to answer these questions. But that is precisely where future investigations will be directed towards.

Conclusion

Because of an intricate and thoughtful study, the Epstein-Barr virus has been found to be one of the causes of multiple sclerosis. As a herpesvirus, EBV can remain in B-lymphocytes after infection indefinitely. While the details are still unknown, some part of the immune system reacts to the presence of this virus and commences the demyelation of neurons, triggering the appearance of MS.

Bibliography

Cdc.gov. 2020. About Epstein-Barr Virus (EBV) | CDC. [online] Available at: https://www.cdc.gov/epstein-barr/about-ebv.html#transmission

Bjornevik, K. et al., 2022. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science, [online] Available at: https://www.science.org/doi/epdf/10.1126/science.abj8222

Lowe, D., 2022. Multiple Sclerosis Causality. [online] Science.org. Available at: https://www.science.org/content/blog-post/multiple-sclerosis-causality

Rivas, R., 2022. La esclerosis múltiple y el virus de la enfermedad del beso: ¿qué es y qué hace el virus de Epstein-Barr?. [online] Nius Diario. Available at: https://www.niusdiario.es/ciencia-y-tecnologia/ciencia/esclerosis-multiple-virus-enfermedad-epstein-barr_18_3266822978.html

Whitley, R., 1996. Herpesviruses. [online] Ncbi.nlm.nih.gov. Available at: https://www.ncbi.nlm.nih.gov/books/NBK8157/

Cover image: https://www.cancertherapyadvisor.com/lymphoma/tackling-ebv-associated-lymphoma-early-research-overall-survival-benefit-donor-transplants/article/811596/

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Lilly Pubillones
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Trinity College Hartford
Biochemistry

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