Epstein-Barr Virus (EBV) is a human-γ herpes virus that has infected more than 90% of the world's population, including more than 95% of healthy adults [1]. Whether you accept it or not, at this moment, EBV is most likely lurking in your body, so EBV infection is called "everyone's disease".
The route of transmission of EBV is mainly through oral contact, so EBV infection is also called "kissing disease". So, what impact will such a high infection rate of the virus have on human health? Is there a vaccine to protect against it? What happens when COVID-19 meets EBV? Pathogens, Science, and Cell have all studied and reported on this, so let's take a look.
Pathogens: Many New Crowns
Sequelae are caused by reactivation of EBV
On June 17, 2021, the World Health Organization and a team of researchers from Brown University and others published a study entitled "Investigation of Long COVID Prevalence and Its Relationship to Epstein-Barr Virus Reactivation" in Pathways (Figure 1). Studies have found that many of the long-term symptoms of COVID may not be the result of a direct action of the SARS-CoV-2 virus, but rather the result of EBV reactivation induced by the COVID-19 virus.
Figure 1 Research results (Source: Pathogens)
A total of 357 participants applied to join the study, of which 185 patients who recovered from COVID-19 were applied for and included in the trial pool, and finally 68 patients with sequelae of COVID-19 were included in the trial. The 68 patients were divided into four groups: two major (long-term) study groups and two secondary (short-term) study groups. The "long-term COVID group" consisted of 30 subjects who tested positive for COVID-19 at least 90 days before enrollment and all of whom reported one or more long-term COVID symptoms used in this study; the "long-term COVID control group" consisted of 20 subjects who tested positive for COVID-19 at least 90 days before enrollment and did not have any long-term SYMPTOMS symptoms; the "short-term COVID group" consisted of 9 subjects, Subjects tested positive for COVID-19 for 21 to 90 days prior to enrollment, and all reported one or more long-term SYMPTOMS symptoms used in this study; the "short-term control group" consisted of 9 subjects. Analysis of blood samples from subjects revealed:
The overall prevalence of long-term COVID was 30.3% (56/185) among participants in the test cell, including 4 patients with COVID-19 who were initially asymptomatic and later developed long-term SYMPTOMS;
2. 66.7% (20/30) of long-term COVID subjects were positive for EBV reactivation of viral capsid antigen (VCA) IgM and 10% (2/20) of control subjects with significant differences;
3. A similar EBV positive ratio was observed in 18 subjects 21-90 days after testing positive for COVID-19, suggesting that reactivation of EBV may occur shortly after or simultaneously with COVID-19 infection.
Jeff Gold, a World Health Organization researcher who has been studying COVID for a long time, said: "It is clear that EBV reactivation may play a role in the long-term consequences of SARS-COV-2 infection, and a series of unexplained sequelae such as fatigue, brain fog, rashes, etc. after the recovery of COVID-19 patients are the same as we expected the consequences of EBV reactivation." ”
Science：EBV
Causes a terminal illness that cannot be cured
On January 13, 2022, a research team from the Harvard School of Public Health published a study titled "Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis" (Figure 2). Studies have found that EBV is the main cause of multiple sclerosis (MS), a blood marker of neurodegenic degeneration, the protein of the light chain of nerve filaments, which increases only after EBV infection.
Figure 2 Research results (Source: Science)
MS is a chronic demyelinating disease of the central nervous system of unknown etiology, when MS appears, the immune system attacks the protective sheath (myelin) that envelops nerve fibers and causes the brain to fail to communicate with other parts of the body, eventually leading to permanent damage or degeneration of the nerves. The signs and symptoms of MS vary widely, depending on the extent of nerve damage and which nerves are affected. Some patients with severe MS may have difficulty or simply not walking independently, while others may require long-term remission without developing any new symptoms (Figure 3). Unfortunately, as an autoimmune disease, MS is currently incurable, and the cause of the disease is unknown, but the scientific team believes that EBV is a possible culprit.
Figure 3 Nervous system-affected MS (Source: Mayo Clinic)
In the study, the research team conducted a 20-year collaborative study with the U.S. military to collect more than 10 million ethnically diverse active-duty U.S. servicemen's blood samples between 1993 and 2013, including 955 case samples diagnosed with MS during service. By analyzing data from blood samples at the beginning of U.S. military service and every two years after service, the scientific hypothesis that MS is caused by EBV was validated. The study found that:
1. EBV-infected servicemen are 32 times more likely to develop MS than uninfected military personnel;
2. The level of the protein of the light chain of nerve filaments, a blood marker of neurodegeneration, which increases only after EBV infection;
3. EBV infection occurs not only before the onset of MS symptoms, but also before the time when MS can detect pathological mechanisms.
Alberto Ascherio, leader of the study, said: "Only a large number of participants in this study will it be possible to prove the association between EBV and MS for the first time. In the past, the high prevalence of EBV in the general population has been a huge obstacle to proving the causal relationship between EBV and MS, and this study shows that EBV is the main cause of MS, but it is clear that other factors are also involved, such as genetic factors in EBV-positive individuals and vitamin D deficiency. For example, most smokers will never develop lung cancer, and just as most people infected with EBV will never develop MS that cannot be cured. ”
Cell: Reactivation of EBV
It is a risk factor for the long-term sequelae of the new crown
On January 24, 2022, James R. Heath, Nobel Laureate of the Washington State Institute for Systems Biology, usa, presented a study entitled "Multiple early factors anticipate post-acute COVID-19 sequelae" (Figure 4). The study found four pre-risk factors for the development of long-term COVID: type II diabetes, SARS-CoV-2 RNA levels in the blood, EBV infection levels, and specific autoantibodies.
Figure 4 Research results (Source: Cell)
Approximately 31% – 69% of people with COVID-19 have long-term COVID, which can last four weeks or more, including memory loss, gastrointestinal distress, fatigue, loss of smell, shortness of breath, and other symptoms. The researchers believe that long-term COVID is related to autoimmune factors and residual viral fragments in the body, so they collected blood and swab samples from 309 PATIENTS with COVID-19 at different time points and performed a comprehensive phenotypic analysis, combined with clinical data and patient-reported symptoms, and conducted in-depth multi-omics, longitudinal surveys. The results found:
1. EBV infecting 90% of the global population is usually inactive in vivo, but is reactivated early after SARS-CoV-2 infection and is significantly associated with the symptoms of long-term sequelae of COVID-19;
2. The presence of specific autoantibodies (associated with autoimmune diseases such as lupus) can lead to long-term COVID in patients;
3. The blood viral load in the early stages of SARS-CoV-2 infection is closely related to the long-term symptoms of COVID-19 that develop after recovery, so the administration of antiviral drugs at a very early stage of the COVID-19 course can potentially prevent long-term COVID;
4. Through the analysis of the participants' electronic health records, it was found that type II diabetes was significantly associated with some long-term COVID.
Dr James R. Heath, corresponding author of the study, said: "Identifying risk factors for long-term COVID is an important step forward, not only to understand the long-term sequelae of COVID-19 and the potential therapies that target it, but also to understand which patients are at the highest risk of developing chronic diseases. These findings also help us think about the effects of other chronic diseases, such as post-acute Lyme syndrome. ”
EBV is accompanied for life
Constant "tug-of-war" with the immune system
1
The discovery of EBV began with cancer
Tumors have been the leading cause of human mortality for thousands of years, but because of the complexity of their roots, effective prevention and treatment measures have not been found. Denis Parsons Burkitt and Michael Anthony discovered the first virus associated with human tumors, EBV, in 1964. Denis Parsons Burkitt often sees abnormal jaw tumors in young children in Uganda, which became Burkitt's lymphoma (Figure 5). Burkitt suspected that the tumor was caused by a pathogen because of its regional spread characteristics, which can spread rapidly in children and double in volume within 24 to 48 hours, filled with white blood cells or cancerous lymphocytes.
Figure 5 A seven-year-old child with Burkitt lymphoma (Source: Mikeblyth)
In the 1970s, Hank Balfour, a virologist at the University of Minnesota School of Medicine, was studying the long-term survival prospects of kidney transplant patients when he noticed that a small percentage of them continued to develop a rare form of cancer, and nearly all of them were infected with a virus called Epstein-Barr. Balfour said: "EBV can be latent in human cells for a long time, quietly assimilating in body tissues, the immune system is almost impossible to clear it, once infected, EBV will accompany us for the rest of our lives." ”
2
Although EBV is usually mild, its pathogenicity should not be underestimated
EBV is a linear double-stranded DNA virus with three basic structures: a nuclear sample, a capsid, and a coating. The target cells first infected by EBV are epithelial cells and B cells, which can evade the immune damage of the host, latent infection in B cells, and can be reactivated and multiplied when the body's immunity is low, causing corresponding diseases, which is a common virus that causes respiratory infections and tumors. EBV persists throughout life, and most people have asymptomatic chronic infections, but immunocompromised patients may not be able to control EBV infection, increasing the risk of severe disease.
Figure 6 Clinical manifestations and pathogenesis of EBV infection (Source: [5])
EBV-related diseases include hematologic-related tumors such as Burrkit lymphoma, Hodgkin lymphoma, diffuse large B-cell lymphoma, NK/T cell lymphoma, post-transplant lymphoproliferative disease, X-linked abnormal lymphocyte hyperplasia, hephagocytic lymphohistosis, systemic EBV-positive T-cell lymphoma, autoimmune diseases such as systemic lupus erythematosus, multisysclerosis, colorectal cancer, gastric cancer and other non-lymphatic tumors, infectious mononucleosis Nasopharyngeal carcinoma, chronic active EBV infection, etc. (Figure 6).
Figure 7 EBV-related diseases (Source: Care Online)
3
How does EBV protect? Is there a vaccine?
As a virus that cannot be removed, we can only work on prevention, so before that, we must first know how EBV is infected. Patients and carriers of EBV are the source of infection, and their salivary glands and saliva are rich in the presence of a large amount of virus, which can be detoxified continuously or intermittently. EBV is transmitted mainly through oral contact, but can also be transmitted by blood transfusion and organ transplantation (Figure 8). Populations are generally susceptible to EBV, and their serologic positive rates in the population can be as high as 90%. EBV infection occurs in all seasons, with more prevalence from late autumn to early spring. The infection is spread around the world, is mostly sporadic, and can be endemic in small areas. In developing countries such as mainland China and Asia, the age of initial infection of EBV is mainly infants and young children, while in developed countries, it is mainly adolescents.
Figure 8 Pathways of conventional EBV infection (Source: Care Online)
The difficult to prevent and carcinogenic properties of EBV put forward a hard demand for vaccine protection, and there is no EBV vaccine on the market worldwide, but pharmaceutical companies have been gearing up. Moderna is the only company in the world that is in the clinical development of an EBV vaccine, and its development route is mRNA vaccine (Figure 9). Moderna's clinical trials targeted people in the 18-30 age group, but given that so many people are infected with EBV in childhood, the ultimate goal is to use the vaccine in infants. Katherine Luzuriaga, head of clinical trials for moderna EBV vaccines, said: "There are very few vaccines that can induce complete immunity, however, an effective EBV vaccine may limit the spread of the virus, prevent an abnormal immune response, and reduce the viral load at the beginning of infection. All of these factors may play a role in downstream disease pathogenesis, not just for MS, but also for cancers associated with EBV. ”
Figure 9 Clinical development of Moderna EBV vaccine (Source: Moderna official website)
When the constantly mutating new crown virus meets the EBV that dresses up as a pig and eats a tiger, it is even worse for human beings who have suffered from diseases, and I hope that the arrival of the new crown vaccine and the EBV vaccine under development can escort our health.
Source: MIMS, for academic exchange only.
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Resources:
[1] Neves M, Marinho-Dias J, Ribeiro J, et al. Epstein-Barr virus strains and variations: Geographic or disease-specific variants? J Med Virol. 2017 Mar;89(3):373-387. doi: 10.1002/jmv.24633. Epub 2016 Dec 5. PMID: 27430663.
[3] Bjornevik K, Cortese M, Healy BC, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 2022 Jan 21;375(6578):296-301. doi: 10.1126/science.abj8222. Epub 2022 Jan 13. PMID: 35025605.
[5]https://slidesplayer.com/slide/11263243/
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