The Complex Relationship of Multiple Sclerosis with Viruses

Author: Jenny M. Willis

The following is a research paper the founder wrote in Spring 2018 during graduate studies while studying molecular virology.

INTRODUCTION

We live in a pivotal time where we have the knowledge and technology to make significant progress in breakthrough solutions that can change the world for Multiple Sclerosis (MS) patients.  More than 2.8 million MS sufferers are hoping scientists find a cure for one of the most elusive and mysterious neurological autoimmune diseases (Casiraghi and Horowitz, 2013), (Getts et al, 2014), (Lebbey and Fujinami, 2010), (Ramasamy et al, 2017), (Rosche et al, 2004).  Some of the hallmark characteristics of MS are demyelination, axonal damage, and inflammation that results in disability (Hassani et al, 2018), (Libbey and Fujinami, 2010), (Mecha, et al, 2013), (Ramasamy et al, 2017), (Willis et al, 2009).  MS is also a chronic neuro-inflammatory condition of the central nervous system (CNS), and there are several different forms of the disease ranging from relapsing-remitting to chronic progressive (Hassani et al, 2018), (Rosche et al, 2004), (Wuest et al, 2014).  Before a cure can be made for any illness, its etiology must first be figured out, and the etiology of MS is still unclear (Mecha, et al, 2013), (Morandi et al, 2015).  We have been searching for the cause of MS rigorously since before 1981 when the first magnetic resonance images (MRIs) of brain lesions were captured (NMSS, 2018).  As we have learned since, MS is a multi-faceted disease with several potential triggers relating to immune, environmental, epidemiological, genetics, and several infectious agents such as viruses and bacteria (Getts et al, 2014), (Hassani et al, 2018), (Libbey and Fujinami, 2010), (NMSS, 2018), (Rosche et al, 2004), (Willis et al, 2009).  The focus of this paper is to survey the literature regarding the role viruses play in MS, and this is important because determining the role of viruses in the etiology and progression of MS may enable us to effectively treat and cure this disabling disease.  

VIRUSES IN GENERAL AS CAUSATIVE AGENT FOR MS

While researching, it became clear that people with MS have internal conditions welcoming to viruses.  Some of the viruses covered in this literature review that have been associated with MS are:  coronavirus, cytomegalovirus (CMV), herpes-simplex viruses 1 and 2 (HSV-1, HSV-2), Epstein-Barr virus (EBV), human herpes-virus-6 (HHV-6), measles, rubella, torque teno virus (TTV), human endogenous retroviruses (HERVs), human T cell lymphotropic virus type I (HTLV-I), John Cunningham virus (JCV), Polio virus, progressive multifocal leukoencephalopathy (PML), and varicella zoster virus (VZV) (Antony et al, 2004), (Banki et al, 1994), (Borkosky et al, 2012), (Morandi et al, 2015), (Olival et al, 2013), (Sotello et al, 2007).  It has been debated for years whether or not viruses play a part in actually causing MS, and even though several viruses are present and/or seem to be involved in the pathogenesis of MS, no single virus has been identified as the specific culprit (Borkosky et al, 2012), (Owens and Bennet, 2012).  However, one virus recently found in inflammatory brain tissues may be enough to establish a connection with the etiology of MS: the Epstein Barr virus (Hassani et al, 2018).  

VIRUSES AS THE START OF MS: Epstein Barr virus, Torque Teno Virus

Research seems to be pointing the start of MS to genetically susceptible people after they are exposed to one or more infectious agents (Hassani et al, 2018), (Owens and Bennett, 2012).  When doing research on MS and viruses for this paper, the Epstein-Barr Virus (EBV) has come up the most.  EBV is a human herpes virus that infects B cells in ~95% of the human population and remains in the memory B cells throughout life (Owens and Bennett, 2012).  In several studies over the past 20 years, EBV has been identified as an environmental trigger and a direct causative agent of CNS immunopathology (Angelini et al, 2013), (Casiraghi and Horowitz, 2013), (Hassani et al, 2018), (Owens and Bennett, 2012). 

However, the EBV has been the focus of much controversy.  This article from 2009 actually supported the other side of the debate, saying that EBV infection is not a characteristic feature of MS; they found considerable evidence that EBV infection is related to developing the disease, but they are not convinced that EBV contributes directly to CNS immunopathology (Willis et al, 2009).  They examined MS white matter brain lesions with B cell infiltrates for EBV infection and did not detect EBV in any of the MS samples, but it was detected in the EBV positive controls (Willis et al, 2009). They also tested a second cohort of MS specimens and only found very low levels in 2 out of 12 samples, so they concluded that CNS EBV infection is rare in MS brains and it is unlikely that EBV infection contributes directly to MS (Willis et al, 2009).

But in 2010 when EBV antibody levels in the serum of MS patients were compared to other neurological diseases, increased amounts of anti-EBV-IgG in the serum and cerebrospinal fluid (CSF) of MS patients was found, giving more evidence that EBV is possibly involved in MS (Nociti et al, 2010). In 2012, we found a clue about what the Epstein-Barr virus may be doing in the brains of people with MS: RNA from the virus could be triggering the inflammation of the nerve tissue (Geddes, 2012).  And if a person becomes infected with EBV and develops a glandular fever, this increases the risk of developing MS (Geddes, 2012).  Post-mortem analysis of MS brains in London not only found the EBV in damaged areas, but when they did antibody tests, they found that the virus released small RNA molecules that could activate the immune system, trigger inflammation, damage nerve cells, and cause MS symptoms (Geddes, 2012).  Although many therapies for MS are not successful for many MS patients, some patients have had success with therapies that are directed at B cells, which led many scientists to believe they could play a central role in MS pathogenesis (Meier et al, 2012).  The data in 2012 seemed to show that B cell depletion led to reduced brain lesions; they also suspected that EBV infected memory B cells, hijacked them as ‘Trojan horses’ and ‘smuggled’ the virus into the CNS (Meier et al, 2012).

Very recently, we have figured out some of the underlying mechanisms that could link the EBV to the pathogenesis of MS.  In a large study, DNA samples and brain tissues tested for EBV revealed EBV in 90% of MS cases and only 24% of non-MS samples; none of the common herpesviruses were detected in the PCR reactions (Hassani et al, 2018).  In qPCR reactions, EBV was low-moderate in most cases, but in 18% of MS cases, EBV was very widespread but scattered (Hassani et al, 2018).  Further analysis of heavily-infected samples revealed an EBV latent protein and an early lytic EBV protein expressed (Hassani et al, 2018).  By 2013, we already knew that EBV can infect and establish itself in B cells, infect other cell types, and activate the immune system by causing pro-inflammatory mediators to be produced (Casiraghi and Horowitz, 2013).  But the link may finally be established because for the first time, when they used double-staining, they were able to see that both astrocytes and microglia (in addition to B cells) were infected (Hassani et al, 2018).  This demonstrates EBV is present and transcriptionally active in the brains of most cases of MS and support EBV’s role in MS pathogenesis (Hassani et al, 2018).          

VIRUSES DURING RELAPSES OF MS: Varicella Zoster Virus and EBV

The EBV may play a role in MS pathogenesis, but what about relapses?  In order to find out if EBV-specific CD8+ T cell response correlates with disease activity in MS, CD8+ T-cell responses to EBV latent and lytic antigens in MS were measured (Angelini et al, 2013).  There were fewer lytic antigen-specific CD8+ T cell responses in people whose MS was in remission, but more during relapses (Angelini et al, 2013).  Post-mortem MS brain samples for EBV lytic proteins and interactions showed infected plasma cells in the brain lesions (Angelini et al, 2013).  This may suggest that if people who have MS but are in remission become infected with EBV, this could potentially cause a relapse (Angelini et al, 2013).

During relapses, other viruses are thought to be active because some patients report having cold sores or other infections during relapse.  One study searched for DNA from several viruses during relapse and remission: VZV, HSV-1, HSV-2, EBV, and HHV6 (Sotelo et al, 2007).  There was DNA from VZV in 95% of MS patients during relapse and 17% during remission, but all of the controls were negative; DNA from HHV6 was detected in 24% of MS patients during relapse and only 2% during remission (Sotelo et al, 2007).  DNA from herpes simplex viruses was not found in any subject, and DNA from EBV was found in about the same amount in all of the groups (Sotelo et al, 2007). In this study, VZV plays a role in MS, but not the other viruses, even though several people with MS report having cold sores during times of relapse.  A follow-up study to the 2007 Sotelo et al. study assessed VZV in MS relapse again, but this time testing the CSF of the patients whose DNA tested high for VZV DNA and compared it to MS patients who were in remission (Sotelo, 2008).  This revealed that the VZV found in the patients' blood and CSF at remission show that VZV has a significant role in identifying the causes of MS relapse (Sotelo, 2008).

Seven years later, the authors did another study trying to determine the specific participation of VZV during relapses (Sotelo et al, 2014).  They tested patients during relapse and remission, and also progressive MS patients (Sotelo et al, 2014).  They found DNA from VZV in the CSF from 100% of the MS patients during relapse and in 90% of the PBMC (Sotelo et al, 2014)!  During relapses, VZV DNA was only found in the CSF of 31% and in the PBMC in only 19% (Sotelo et al, 2014).  In the progressive MS samples, they found VZV DNA in the CSF in 83% and PBMC in 33% (Sotelo et al, 2014).  VZV was not found in any of the controls.  The results seem convincing that VZV plays a role during MS relapses and could be involved in the etiopathogenesis of MS (Sotelo et al, 2014). 

VIRUSES INVOLVED IN DIAGNOSING MS: Varicella Zoster, Measles, Rubella

Diagnosing MS is not easy because patients have a first episode of neurologic symptoms characteristic of MS but they have not yet been diagnosed; this is called clinically isolated syndrome (CIS) (NMSS, 2018).  Some people will have an episode of CIS and nothing follows, but ~80% of the time, a relapse happens.  To diagnose MS, an MRI of the brain is done and lesions must be present; also, testing for myelin basic protein and oligoclonal bands in the CSF (NMSS, 2018).  There is a reaction called the measles, rubella, and varicella zoster virus reaction (MRZR) common with MS, a study compared MRZR results to oligoclonal bands and MRI brain scans to see if MRZR could predict which CIS patients will develop MS (Brettschneider et al, 2009). With MRZR, people with MS have a certain B cell response to neurotropic viruses and their antibodies able to be measured in the CSF (Brettschneider et al, 2009).  MRZR markers were significantly higher in the patients that developed relapsing-remitting MS, indicating the ability to predict when CIS will develop into MS (Brettschneider et al, 2009). 

CONTROVERSY: Varicella Zoster Virus and Cytomegalovirus

There has been much controversy surrounding the role of CMV and VZV in the pathogenesis of MS.  A very large study with 800 MS patients and 1,000 healthy controls found higher levels of anti-CMV IgG and anti-VZV IgG in people with relapsing-remitting MS and concluded that those viruses play a key role in the pathogenesis of MS (Karampoor et al, 2017). But these conclusions were reached by testing serum using ELISA, an enzyme-linked immunosorbent assay technique used to detect things like proteins and antibodies (Badihian et al, 2017).  This information conflicts with a 2009 study using CSF and PCR to test for VZV DNA and IgG (Badihian et al, 2017).  There was no herpes or VZV DNA in the samples, so they concluded that VZV antigens do not play a role in the pathogenesis of MS and the antigen activity they found was probably from other viruses like the EBV and rubella (Badihian et al, 2017).  They argue that ELISA does not provide enough evidence to claim they are involved MS pathogenesis , and defend their stance using other studies that showed negative association between CMV serum and MS risk (Badihian et al, 2017), (Sundqvist et al, 2014), (Zivadinov et al, 2006).  This goes along with an earlier study where Angelini et al. found no difference in the CD8+ T cell response to cytomegalovirus between healthy donors and MS patients, regardless of whether they were actively relapsing or in remission (Angelini et al, 2013).  So although in some studies the CMV was active, there are other studies that disagree, and there is much controversy surrounding CMV in MS.

REACTION TO MEDICATIONS: Varicella Zoster Virus and John Cunningham Virus

There are several accounts of people with MS taking medicines and then contracting viral infections during treatment; I will discuss only two drugs on the market for relapsing-remitting MS: Fingolimod and natalizumab.  Fingolimod works by interfering with S1P receptor signaling (Harrer et al, 2015).  There was a case where an MS patient taking Fingolimod became infected with VZV, so the patient had to stop taking Fingolimod and start taking antivirals (Harrer et al, 2015).  Tests showed double the amount of VZV-specific IgG, elevated CD4+ T cells, and increased lymphocytes counts (Harrer et al, 2015).  There were also differences in the CSF nine days after stopping Fingolimod treatment (Harrer et al, 2015). 

Follow-up to this incident came along a couple of years later because since VZV infection is now implicated in MS but VZV actually causing MS disease pathogenesis is disputed, there is a risk for people taking Fingolimod to have serious VZV complications (Manouchehrinia et al, 2017).  To assess the risk for complications, questionnaires were distributed to MS patients: 86% of the people reported that they had a history of VZV and 17% had repeat zoster episodes (Manouchehrinia et al, 2017).  Out of the repeat zoster episodes, 48 out of 51 patients tested seropositive for VZV IgG, which is comparable with previous data (Manouchehrinia et al, 2017).  Because so many people with MS have had single or multiple occurrences of zoster, special consideration should be given to immunosuppressive therapies and VZV vaccines (Manouchehrinia et al, 2017).     

The John Cunningham virus (JCV) is another example of how people with multiple sclerosis seem to provide perfect conditions for viruses to thrive.  People with MS taking natalizumab have a risk of developing progressive multifocal leukoencephalopathy (PML), which is caused by JCV (Achiron et al, 2016).  It is believed that for many MS patients taking natalizumab, a serological conversion occurs and they go from anti-JCV antibody-negative to anti-JCV antibody-positive status, termed ‘JCV switching’ (Achiron et al, 2016).  Genetic testing to find out if MS patients are predisposed to antibody switch when on natalizumab treatment found changes in anti-JCV antibody-negative MS patients, so they tested their blood transcriptional profiles: after 3 years of taking natalizumab, ~25% of the MS patients who were anti-JCV antibody-negative actually switched to become anti-JCV antibody-positive (Achiron et al, 2016)!  In JCV switchers, natalizumab caused 946 significantly differentiating genes and in non-switchers, the medicine induced 1186 differentiating genes (Achiron et al, 2016).  In the JCV switchers, there was over-expression of genes related to viral entry and endocytosis pathways (Achiron et al, 2016).  They also found specific genetic sequences that can identify which MS patients are predisposed to become JCV switchers (Achiron et al, 2016).  These are great results because they can potentially help identify which MS patients can use natalizumab treatment and not be at risk to develop PML, which is life-threatening.

VIRUSES AS ENVIRONMENTAL TRIGGERS FOR MS – Demyelination

Viruses can infect cells outside (peripheral) or inside the CNS, and they are associated with demyelination (Libbey and Fujinami, 2010).  MS sufferers are commonly infected with several viruses such as peripheral Torque Teno virus (TTV), peripheral and internal CNS EBV, and internal CNS infections of HHV-6 (Libbey and Fujinami, 2010).  If the CNS becomes infected with multiple viruses, this can prime the immune system and trigger disease, but if the infections are outside of the CNS, this leads to inflammation within the CNS, and the result is demyelination (Libbey and Fujinami, 2010).  If neurotropic viruses get into the CNS by crossing the blood-brain barrier (BBB), inflammation will occur because there are too many cytokines, and the BBB breaks down (Miner and Diamond, 2016).  The BBB is made of several different types of specialized cells, and they all work together to prevent pathogens, immune cells, and soluble molecules from getting into the CNS (Miner and Diamond, 2016).  If pathogens do get through the BBB, they can infect the CNS, causing inflammation and demyelination (Miner and Diamond, 2016).  A study investigated EBV and TTV as possible candidates involved in the pathogenesis of MS (Borkosky et al, 2012).  They measured viral replication of two different TTV isolates from MS brains in both EBV-positive and negative cell lines (Borkosky et al, 2012).  Their findings suggest that there is a helper relationship between the two viruses: EBV infections help TTV replicate, which suggests that these two viruses may be involved in the etiology and progression of MS (Borkosky et al, 2012).

RETROVIRUSES AND GENETICS: the MS Trigger

We are still not sure of the exact cause of MS but there is strong evidence pointing to having a genetic predisposition associated with certain environmental factors that can trigger the disease (Banki et al, 1994), (Casiraghi and Horowitz, 2013), (Morandi et al, 2015), (Willis et al, 2009).  An estimated 30 million years ago, exogenous retroviruses are thought to have integrated themselves into human germ line cells (Morandi et al, 2015), (Olival et al, 2013).  This is how they may have originally become part of human DNA and began to be preserved throughout the generations (Morandi et al, 2015).  Once integrated, they were termed human endogenous retroviruses (HERVs), and they make up about 8% of the human genome; in most people, they are either silent or barely expressed, but unfortunately, for people with MS, HERVs are highly expressed (Antony et al, 2004), (Morandi et al, 2015), (Olival et al, 2013).  The envelope protein of the MS-associated retrovirus from the HERV-W family has shown the most evidence to trigger MS, and the increased HERV gene activity occurs in immunologically activated glia and is expressed in the monocytes and microglia of the lesions found in brains of MS patients (Antony et al, 2004), (Morandi et al, 2015).  People with MS usually have higher levels of envelope transcripts from HERV-W in their CSF, plasma, and brain tissues (Olival et al, 2013).  When the HERV-W it is activated, it produces inflammatory cytokines, reduction of myelin protein expression, death of oligodendrocyte precursors, and plaques form in the brain (Morandi et al, 2015), (Olival et al, 2013).  This adds additional support to the idea that endogenous retroviruses play a role in MS pathogenesis through the immune system (Banki et al, 1994), (Olival et al, 2013).

VIRUSES: Autoimmunity, Molecular Mimicry, Retroviruses

Although the etiology of multiple sclerosis is not very well understood, molecular mimicry between myelin proteins and internal retroviral proteins is being proposed (Banki et al, 1994), (Morandi et al, 2015), (Ramasamy et al, 2017).  Molecular mimicry is an interesting concept because it describes the possibility that two molecules, one from the body and the other from a foreign pathogen, are so similar that the body gets confused, and so the immune system reacts (Banki et al, 1994).  When the immune response happens in MS, it targets specific molecules like myelin basic protein, myelin oligodendrocyte glycoprotein, and proteolipid protein (Ramasamy et al, 2017).

One earlier attempt to connect MS with molecular mimicry deals with the human T cell lymphotropic virus type I (HTLV-I), which is a human retrotransposon (Banki et al, 1994).  They cloned it and found it plays an important role in the coding sequence of the human transaldolase gene (TAL-H), which is involved in lipid biosynthesis (Banki et al, 1994).  Analysis of human brain sections and cell cultures showed that TAL-H is possibly linked to production of large amounts of lipids as a major component of myelin and protecting the myelin sheath from oxygen radicals (Banki et al, 1994). They also linked similar sequences between TAL-H and core human retrovirus proteins, suggesting that molecular mimicry between viral core proteins and TAL-H can lead to infection and destruction of oligodendrocytes in MS (Banki et al, 1994).

More recently, two alleles, DRB1*1501 and DRB5*0101, combined with the expression of human internal retroviral envelope proteins, have been linked to MS but the molecular mechanisms that explain how was unclear, so a study performed sequence homologies of everything: the two alleles, the retroviral envelope, the myelin proteins, and the in silico predictions of peptides derived from them that can bind to the two alleles (Ramasamy et al, 2017).  They found that there was molecular mimicry taking place between the peptide epitopes from the envelope proteins of the Human Endogenous Retrovirus W (HERV-W) family of endogenous retroviruses and myelin proteins (Ramsamy et al, 2017).  Specifically, mimicry between myelin protein and syscytin-1, a HERV-W envelope protein only expressed during pregnancy, which could explain why more females are affected by MS ; they think this could be a possible trigger for multiple sclerosis (Miner and Diamond, 2012), (Ramasamy et al, 2017).  Syncytin is upregulated in glial cells located in lesions of MS patients (Antony et al, 2004).  In a previous study, syncytins in astrocytes caused redox reactants to be released, which caused neuroinflammation, which caused oligodendrocytes to die, suggesting that an endogenous retrovirus protein is involved in the demyelination process (Antony et al, 2004).

VIRUSES AS DECOY OF THE IMMUNE SYSTEM: Autoimmunity

The precise trigger for autoimmunity is unknown, and although genetics clearly plays a significant role, it is likely a combination of several factors, including infection (Getts et al, 2014), (Hassani et al, 2018), (Libbey and Fujinami, 2010), (NMSS, 2018), (Rosche et al, 2004), (Willis et al, 2009).  There are a couple of mechanisms identified that might explain how infection sets off the autoimmune response: cross-reactive T cell recognition (also called molecular mimicry), and T cell activation that causes epitope spreading (Getts et al, 2014).  In people with MS, the EBV is present in high amounts in serum, and if a person ever becomes infected with mononucleosis, they are at a higher risk of developing MS (Angelini et al, 2013), (Casiraghi and Horowitz, 2013).  Other scientists suspect that the aggressive autoimmune responses in MS happen because of an imbalance between immune cells and cytokine production during infections, so they did a study to try and address this in Sardinia, Italy, which is an area where MS is rampant (Sanna et al, 2008).  They tested the mononuclear cells of MS patients and controls to measure specific antigen expressions and inflammatory markers before and after infection with HSV-1 (Sanna et al, 2008).  Their results agreed with Owens and Bennet (2012) because they showed that when people with MS are infected with viruses, not only do they have reduced immune responses, but their immune cells are altered (Senna et al, 2008). 

VIRAL GENETICS: Herpes, Polio, Epstein Barr Virus

A 2004 study focused on the Polio Virus Receptor (PVR) and Herpesvirus entry mediator B (HVEB) receptor genes and the chromosome they are on because it was at one point thought to be linked to MS (Rosche et al, 2004).  This was logical to study because both receptors are expressed in the brain and immune system, and they are important for cell adhesion and viral entry (Rosche et al, 2004).  They were able to identify four new polymorphisms in the PVR gene: all of them changed the amino acid sequence of the receptor (Rosche et al, 2004).  Aside from that, they did not find any differences in the expression of the polymorphisms between MS patients and controls, so they couldn’t identify a role of HVEB and PVR genes in developing MS (Rosche et al, 2004). 

Part of the reason MS remains so mysterious is that we don’t know specifically what are the antigenic targets or cell populations that cause the CNS tissue destruction we observe (Owens and Bennet, 2012), (Wuest et al, 2014).  One study attempted to figure out antigen (Ag)-specificity and phenotype of CD4+ and CD8+ T cells of people with relapsing-remitting and chronic progressive MS (Wuest et al, 2014).  They found high levels of EBV and HHV6 activity in the Th-1 phenotype of all patients, and the herpes virus reactivities were more pronounced in the MS patients (Wuest et al, 2014).     

ANOTHER SUSPECT: Coronavirus

The coronavirus has been a suspect in playing a role in MS for nearly 40 years, but no direct link has been established.  A 1980 study isolated two coronaviruses from MS brains and found that the MS patients had higher concentrations of serum antibody than controls (Burks et al, 1980).  They thought that coronaviruses should be considered to have a part in the etiology of MS (Burks et al, 1980).  Since the 1980 study was only 2 samples, they did a larger study and tested them for antibodies against two different human coronaviruses, but they found no significant differences between the MS patients and normal subjects (Hovanec and Flanagan, 1983).  Later, another large coronavirus study took brain tissue and tested them for human coronaviral RNA (Dessau et al, 2001).  They found sporadic PCR positives in both groups in some of the assays, but their results were not reproducible and there wasn’t any difference in the proportion of positive signals from the MS patients compared to controls (Dessau et al, 2001).  So they didn’t find any evidence that a chronic infection with those two strains of the human coronaviruses can be linked to MS (Dessau et al, 2001).  Even though coronavirus is not directly linked to MS, the pattern remains that viruses keep mysteriously popping up in people with MS at various times. 

VIRAL MODELS OF MS: Theiler’s Virus

Because MS has immunopathological mechanisms, a good way to study the disease is through animal models that use viruses to reproduce chronic demyelination and axonal damage (Mack et al, 2003), (Mecha et al, 2013). The Theiler’s murine encephalomyelitis virus (TMEV) model is commonly used to study the more aggressive form of MS because it produces a chronic progressive disease similar to MS, allowing us to study axonal damage, neuro-inflammation, and epitope spread from viral to myelin (Mack et al, 2003), (Mecha et al, 2013). From the TMEV model, we have learned that human microglia play an important role in antigen presentation at the very start of clinical symptoms and contribute to myelin destruction (Mack et al, 2003).

CONCLUSION

One of the overarching themes throughout this study is that when people with MS are infected with viruses, not only do they have reduced immune responses, their immune cells are altered and they are generally susceptible to viral infections (Senna et al, 2008).  I found two main viruses that play a major role in MS etiology relapses: EBV and VZV.  The most data pointing to a causal link has been on the EBV, and it is believed that if we can pinpoint EBV as a trigger, it’s possible that we could potentially prevent the condition by treating the virus (Geddes, 2012).  Since EBV is present and transcriptionally active in the brain of most cases of MS, this could support a role for the virus in MS pathogenesis (Hassani et al, 2018).  The most compelling data gathered surrounding VZV say that it plays a pretty big role in relapses (Sotelo et al, 2014).  Also, since gastrointestinal microbiota modulate BBB function, improving gastrointestinal microbiota health (like taking a probiotic) may be beneficial for people with MS (Miner and Diamond, 2016), (NMSS, 2018).

So many people are so quick to reject nutritional recommendations for chronic diseases, but there are some supplements that have been found in studies to combat Epstein Barr virus including: vitamin C, zinc, olive leaf extract, vitamin D, quercetin, curcumin, astaxanthin, lauricidin, selenium, and others (Dobberstein, 2018).   Since there is no cure for MS, nutritional support seems like the way to go for management and prevention in genetically susceptible individuals.  If it really is true that the Epstein Barr virus plays a major role in the etiology of MS, then it is worth figuring out every aspect of it, and nutrition shouldn’t be ruled out. Linking nutrition and EBV, a new study focuses on EBV and nutrition with two nutrients, EGCG (epigallocatechin-3-gallate) and NAC (N-acetyl cysteine) (Dobberstein, 2018).   EGCG is from green tea extract  and can be used to help manage viruses like EBV by blocking EBV replication signals and downregulating EBV membrane protein 1 (LMP1) (Dobberstein, 2018).  The antioxidant NAC can also block the EBV LMP1, and helps produce glutathione; NAC supplementation reduced inflammation and pathological changes associated with EBV LMP1 (Dobberstein, 2018).  These two antioxidants could be used to treat chronic inflammatory illnesses because they ‘clean-up’ the mess that EBV leaves behind (Dobberstein, 2018).  The EBV membrane protein is proinflammatory, regulates its own activity, and affects host gene expression, so even if the EBV infection is treated, the inflammation the LMP1 leaves behind can create a ripple effect and continue damaging, sort of like a storm  where flooding occurs afterwards (Dobberstein, 2018).        

In summary, the main points of this research are: MS is a complex, multi-faceted, elusive disease; there are many different forms of MS; there are several viruses involved in MS; some of the MS medications are only effective for some of people with MS; some MS medications have undesirable side effects for some people with MS; people with MS provide perfect conditions for viruses to thrive (Achiron et al, 2016), (Casiraghi and Horowitz, 2013), (Getts et al, 2014), (Harrer et al, 2015), (Lebbey and Fujinami, 2010), (Ramasamy et al, 2017), (Rosche et al, 2004), (Sotelo et al, 2007).  After analyzing all of this information, I think the best course of action is to continue doing research to piece together the clues.  If we study which genes are involved in the viruses that are key players in MS, we can develop genetic testing techniques to determine which medicines are good for which subsets of people with MS and thereby avoid the undesirable side effects of the current medications.  Also, while scientists are still piecing together the MS puzzle to find a cure, I think the best option for people who either have MS or are predisposed to developing it would be to use nutrition and supplements that help create an unfavorable host environment in the body so viruses cannot coexist inside of them.  

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