Epstein Barr Virus & Links with COVID-19 and Other Immune Challenges

Epstein-Barr virus (EBV), the first human tumour virus discovered, was discovered approximately 50 years ago and is one of the most common human viruses, found world-wide.  According to the CDC, about 90% of adults have antibodies that show they have a current or past EBV infection.

EBV is a member of the herpesvirus family.  Also known as HPV-4, EBV is a γ-herpesvirus. Gamma-herpesviruses reproduce at a more variable rate than other types of herpesviruses, but share many characteristics in common with other herpes types (alpha- and beta-herpesviruses) particularly with relation to lytic viral replication (the lytic cycle results in destruction/death of infected cells and membranes).  Kaposi’s sarcoma-associated herpesvirus (KSHV, or HHV-8) is another gamma-herpesvirus.

Gamma-herpesviruses were first distinguished by their cellular tropism for lymphocytes and have capacity to induce lymphoproliferation and cancers.[i]  Tumours caused by EBV and KSHV include lymphoproliferative diseases and lymphomas; for example, EBV associates with Burkitt lymphoma and Hodgkin’s lymphoma. EBV also associates with other diseases including cancers such as nasopharyngeal cancer, and with higher risks of developing some autoimmune diseases (e.g. rheumatoid arthritis, Sjögren’s syndrome, SLE and MS.[ii]  EBV-infected cells have been shown to reside within the brain lesions of MS patients.[iii]  

Although there had been considerable evidence indicating the role of viruses in human cancers in animals, identification of EBV association with Burkitt lymphoma led, not only to the discovery of EBV, but also clarified the role of viruses in human cancers.[iv] Since its first discovery, EBV has been studied extensively and is implicated in the aetiology of an unexpectedly diverse range of malignancies.[v] 

EBV, like many viruses (including SARS-CoV-2), spreads most commonly via bodily fluids, primarily saliva, and can cause infectious mononucleosis (‘mono’) and other illnesses. Known also as glandular fever, or ‘kissing disease’, symptoms include fatigue, fever, rash, inflamed throat, swollen lymph nodes, enlarged spleen, and swollen liver.  When contracted in childhood, often there are no symptoms (or no symptoms specifically different from other mild childhood illnesses). Distinguishable symptoms are more common in teenagers and adults who may be unwell for 2-4 weeks and may continue to feel unwell or fatigued for weeks or months.

Although the primary transmission is via saliva, EBV can also spread through blood, semen and organ transplantations. Sharing a toothbrush or drinking glass (and toys for young drooling children) also poses risk.  The virus probably survives as long as the object remains moist.

After 2 years of listening to news about COVID-19 and the Sars-CoV-2 virus, many are familiar with how viruses infect, and with some virology terminology.  Sars-CoV-2 is a coronavirus which falls into Class IV of the Baltimore Classification System, along with polio virus and West Nile virus.  These are single-stranded RNA viruses that make complementary RNA strands to use as template before they can replicate.  All the herpesviruses (including EBV, HSV-1, HSV-2, cytomegalovirus, and varicellovirus that causes chickenpox/shingles) and HPV (human papillomavirus) are Class I in this classification system.  Class I viruses operate like cellular organisms, have double-stranded DNA used as a direct template for mRNA.

Herpesviruses are also considered encephalitis viral infections (as opposed to respiratory viral infections such as coronaviruses, influenza, and rhinoviruses).  Encephalitis virus symptoms include headache, light sensitivity, high temperature, stiff neck/back, vomiting, confusion, and sometimes seizures. Measles and rubella are 2 other types of encephalitis viral infection.

Herpesviruses (including EBV) and coronaviruses (including SARS-CoV-2) are enveloped viruses. This means they have capsids (viral protein shells) coated with a lipid membrane that mediates binding to host cells and may help the virus avoid host immune systems, enabling it to readily spread elsewhere.

Viruses learn to use the host’s normal receptors to its own advantage.  Each virus has its specific receptor with which it has affinity.  Cold and flu viruses target cells lining the respiratory tract, foodborne viruses target cells of the digestive tract and EBV preferentially infects B-lymphocytes via their CD21 surface receptors. In EBV, infection of epithelial cells also occurs but much less efficiently. Significantly, EBV exploits the physiology of normal B-cell differentiation to persist within the memory-B-cell pool of the immunocompetent host.[vi]

Viruses, possibly the most abundant biological entities on Earth, are very small and very robust, with ability to survive extreme conditions, but incapable of reproducing without a host.  Although very small, they are more difficult to kill than bacteria which are generally much larger. Some viruses have capacity to remain always in their host, in dormant (latent) state, and with ability to reactivate.  EBV, like the other herpesviruses, have this capacity to reactivate.

Those with weakened immune systems are more likely to have reactivation symptoms. Reactivation associates with stress which might include from other viral infections (which is one reason why COVID-19 infection associates with EBV reactivation[vii]), nerve trauma, physiological and physical changes (menstruation, fever, exposure to sunlight), and immunosuppression. The true site of latent infection for EBV has not been determined, but EBV likely resides in B-lymphocytes; other potential sites include bone marrow, lymph nodes or other lymphoid organs.[viii]

Since less-than-optimum immune health associates with reactivation symptoms, supporting immune function is a sensible precaution to avoid EBV reactivation. More specifically, inhibition of the lytic cycle (via inhibiting expression of EBV lytic proteins) prevents the EBV virus from producing mature viral particles. This is important, not only for avoiding EBV reactivation, but also with respect to EBV association with lymphoproliferative diseases and lymphomas.

A 2021 study in Oncology Research discusses EGCG (epigallocatechin gallate) inhibition of EBV lytic replication.  LMP1 (latent membrane protein 1, expression of which is related to viral lytic replication in EBV) plays an oncogenic role in viral latent infection of EBV. This study provided first evidence that EGCG directly targets the viral membrane LMP1 and reports the binding and inhibitory efficacy of EGCG to the LMP1, thus suggesting potential benefit via suppressing viral replication.[ix]  EGCG is a broad-spectrum attachment inhibitor and has anti-infective properties as well as antiviral activity. Green Matcha tea powder is EGCG-rich.

Other botanicals show anti-EBV activity. Kalmegh (Andrographis paniculata) effectively inhibited the expression of EBV lytic proteins according to a 2008 study which determined Kalmegh to be potentially useful for its anti-EBV activity.[x]  And Pau d’Arco (Tabebuia impetiginosa), is active against several viral strains including herpes viral strains. Its active constituent lapachol inhibits replication of members of the herpesvirus group including HPV4 (EBV).[xi]

Turmeric (Curcuma longa) was found to exhibit the most potent (of 32 herbs) anti-EBV-EA (EBV early antigen) activity in Raji cells (line of lymphoblast-like cells used in research); this study found turmeric had more than 10 times the anti-EBV activity than passionflower (the 2nd in order of activity).[xii]

Flavones of broad-spectrum antiviral Chinese Skullcap (Scutellaria baicalensis) also showed remarkable inhibitory effects on EBV-EA activation.[xiii]  A British Journal of Cancer study showed ginger species, including Zingiber officinale, contain naturally-occurring compounds that inhibit EBV activation.[xiv] Also, usnic acid (found in Usnea barbata) strongly inhibits EBV activation.[xv]

Four tannins isolated from active fractions of Eugenia uniflora (Pitanga, Brazilian Cherry) were found to have inhibitory effect on EBV.[xvi] Phytochemicals in Tayuya (tea used by indigenous peoples of the Amazon basin) have shown significant inhibitory effects on EBV.[xvii] Cecropia strigosa (Takuna) is another South American botanical with antiviral effect against herpesviruses.[xviii]

Lymphatic system symptoms of EBV (enlarged lymph nodes/spleen) might be addressed with botanical lymphagogue Ceanothus americanus (Red Root)[xix] and Japanese Knotweed (alterative botanical for the lymphatic system). Manayupa (Desmodium molliculum, aka Burbur) may aid as blood cleanser and lymphatic detoxifier. These botanicals which support lymphatic system detoxification, and glycyrrhizic acid (from liquorice) which can reduce the ability of EBV to infect additional cells,[xx] are recommended as useful adjuncts to antiviral botanicals re EBV.

SARS-CoV-2 caught (much of) the world off-guard. The emergence of so many new and old pathogenic viruses should be of concern; understanding some of the contributing factors may help.  Contributory factors in the emergence and spread of viruses include: demographic changes (e.g. migration, urbanization, increased population/population density); medical care and technology (e.g. concentrated microbial intermingling in hospitals/nursing homes, viral/antibiotic resistance); economic and commercial trends (e.g. world-wide disbursement of commercial food animals/food plants/agricultural pharmaceuticals, overly extensive industrial agriculture with resultant damage of ecosystem homeodynamics); ecosystem disturbance (e.g. deforestation, irrigation/waterway disturbances); and climatic changes (e.g. global warming).

The current population density and crowding in inner cities, and in hospitals, nursing homes and prisons, as well as greater use of day-care centres, the very rapid movement of people via air travel and the factory faming of pigs and chickens which increases the virulence of viruses, increases the propensity for future pandemics.  Pharmaceutical antivirals are only partially effective and stocks likely insufficient to deal with pandemics. Vaccines require time and research.  It is imperative to promote immune health support via healthy diets, lifestyle and supplements (including vitamin D, vitamin C and immune-supporting botanicals).  The impact of stress on immune health is well documented; adaptogenic botanicals like Rhodiola, Schisandra, and Maca may be beneficial alongside use of the botanical antivirals mentioned above.

Ninety percent of adults carry EBV.

These are challenging times; we must ALL aim for immunological fitness.

 

[i] Longnecker R, Neipel F (2007) Chapter 22 Introduction to the human γ-herpesviruses, in Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis, Arvin A, Campadelli-Fiume G, Mocarski E, et al, editors. Cambridge: Cambridge University Press.  Available online: Introduction to the human γ-herpesviruses - Human Herpesviruses - NCBI Bookshelf (nih.gov)

[ii] Draborg A, Izarzugaza JMG, Houen G (2016) How compelling are the data for Epstein-Barr virus being a trigger for systemic lupus and other autoimmune diseases? Curr Opin Rheumatol 28(4):398-404.

[iii] Moreno MA, Or-Geva N, Aftab BT, Khanna R, Croze E, Steinman L, Han MH (2018) Molecular signature of Epstein-Barr virus infection in MS brain lesions. Neurol Neuroimmunol Neuroinflamm 5(4):e466.

[iv] Longnecker R, Neipel F (2007) Chapter 22 Introduction to the human γ-herpesviruses, in Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis, Arvin A, Campadelli-Fiume G, Mocarski E, et al, editors. Cambridge: Cambridge University Press.  Available online: Introduction to the human γ-herpesviruses - Human Herpesviruses - NCBI Bookshelf (nih.gov)

[v] Young LS, Rickinson AB (2004) Epstein-Barr Virus: 40 Years On. Nature Reviews 4:757-768.

[vi] Young LS, Rickinson AB (2004) Epstein-Barr Virus: 40 Years On. Nature Reviews 4:757-768.

[vii] Chen T, Song J, Liu H, Zheng H, Chen C (2021) Positive Epstein-Barr virus detection in coronavirus disease 2019 (COVID-19) patients. Sci Rep 11:10902.

[viii] Longnecker R, Neipel F (2007) Chapter 22 Introduction to the human γ-herpesviruses, in Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis, Arvin A, Campadelli-Fiume G, Mocarski E, et al, editors. Cambridge: Cambridge University Press.  Available online: Introduction to the human γ-herpesviruses - Human Herpesviruses - NCBI Bookshelf (nih.gov)

[ix] Li H, Li Y,Hu J et al (2021) (-)-Epigallocatechin-3-Gallate Inhibits EBV Lytic Replication via Targeting LMP1-Mediated MAPK Signal Axes. Oncology Research 28:763—778.

[x] Lin T-P, Chen S-Y, Duh P-D, Chang L-K, Liu Y-N (2008) Inhibition of the Epstein-Barr Virus Lytic Cycle by Andrographolide. Biol Pharm Bull 31(11)2018-2023.

[xi] Lewis WH, Okunade AL, Elvin-Lewis MPF (2005) Pau d’Arco or Lapacho (Tabebuia) in Encyclopedia of Dietary Supplements, edited by Coates PM, Blackman MR, Cragg GM, Levine M, Moss J, White JD (2005) New York: Marcel Dekker.

[xii] Kapadia GJ, Azuine MA, Tokuda H, Hang E, Mukainaka T, Hishino H, Sridhar R (2002) Inhibitory effect of herbal remedies on 12-o-tetradecanolphorbol-13-acetate-promoted Epstein-Barr virus early antigen activation. Pharmacological Research 45(3):213-220.

[xiii] Konoshima T, Kodumai M, Kozuka M, et al (1992) Studies on inhibitors of skin tumor promotion. XI. Inhibitory effects of flavonoids from Scutellaria baicalensis on Epstein-Barr virus activation and their anti-tumor-promoting activities. Chem Pharm Bull (Tokyo) 40(2):531-533.

[xiv] Vimala S, Norhanom AW, Yadav M (1999) Anti-tumour promoter activity in Malaysian ginger rhizobia used in traditional medicine. British Journal of Cancer 80(1/2):110-116.

[xv] Yamamoto Y Miura Y, Kinoshita Y, et al (1995) Screening of Tissue Cultres and Thalli of Lichens and Some of Their Active Constituents for Inhibitio of Tumor Promoter-Induced Epstein-Barr Virus Activation. Chem Pharm Bull 43(8):1388-1390.

[xvi] Lee M-H, Chiou J-F, Yen K-Y, Yang L-L (2000) EBV DNA polymerase inhibition of tannins from Eugenia uniflora. Cancer Letters 154(2):131-136.

[xvii] Konoshima T, Takasaki M, Tatsumoto T et al (1994) Inhibitory effects of cucurbitane triterpenoids on Epstein-Barr virus activation and two-stage carcinogenesis of skin tumors. Biol Pham Bull 17(5):668-671.

[xviii] Silva IT, Costa GM, Stoco PH et al (2010) In vitro antiherpes effects of C-glycosylflavoid-enriched fraction of Cecropia glaziovii Seth. Letters in Applied Microbiology 51:143-148.

[xix] Palanisamy JK, Ponnu S, Mani S, Balakrishnan S (2018) A Critical Review of Traditional Herbal Drugs: An Emerging Alternative Drug for Varicose Veins. World Journal of Pharmacological Research 7(5):316-338.

[xx] Bentz GL, Lowrey AJ, Horne DC et al (2019) Using glycyrrhizic acid to target sumoylation processes during Epstein-Barr virus latency. PLOS ONE 14(5):e0217578