Epstein-Barr Virus Infection in the Development of Neurological Disorders

Abstract

Epstein-Barr Virus (EBV) is a ubiquitous human herpesvirus that contributes to the etiology of diverse human cancers and auto-immune diseases. EBV establishes a relatively benign, long-term latent infection in over 90 percent of the adult population. Yet, it also increases risk for certain cancers and auto-immune disorders depending on complex viral, host, and environmental factors that are only partly understood. EBV latent infection is found predominantly in memory B-cells, but the natural infection cycle and pathological aberrations enable EBV to infect numerous other cell types, including oral, nasopharyngeal, and gastric epithelia, B-, T-, and NK-lymphoid cells, myocytes, adipocytes, astrocytes, and neurons. EBV infected cells, free virus, and gene products can also be found in the CNS. In addition to the direct effects of EBV on infected cells and tissue, the effect of chronic EBV infection on the immune system is also thought to contribute to pathogenesis, especially auto-immune disease. Here, we review properties of EBV infection that may shed light on its potential pathogenic role in neurological disorders.

Keywords: CNS; Epstein-barr virus; PCNLS; encephalitis; latent infection; lytic infection; multiple sclerosis.

Figure 1.

EBV-encoded small RNA in situ hybridization EBER ISH in a murine xenograft model of EBV-associated lymphoma (40X).

Figure 2.

Consequences of EBV Infection over the human lifespan

Figure 3.

Mechanisms of EBV neuroinvasion and virus mediated damage in the CNS. EBV may enter the brain via normal B cell trafficking or through infection of brain microvasculature endothelial cells (BMVEC). Either endothelial cells of the neurovasculature or infected B cells may be the source of neurotoxicity through the release of inflammatory cytokines and viral proteins. In addition, T-cell mediated responses to infected cells in the brain may lead to bystander damage. Alternatively, molecular mimicry, where similarities between EBV and host-peptides results in the cross-activation of autoreactive T or B cells may be involved in the neuropathogenesis of EBV-associated disorders of the CNS.A less favored hypothesis suggests that EBV infection of neurons and lytic gene expression leads to neuronal damage.

Figure 4.

Possible mechanisms for EBV as an etiologic or disease-modifying agent in multiple sclerosis. Several possible hypotheses have been proposed for EBV as a mediator of CNS damage and disease in MS and it is likely that the interplay between host and viral determinants are involved. Viral determinants may include: 1. the EBV latency proteins EBNA1, the master regulator of EBV latency and an important pro-survival factor, and EBNA2, which is involved in B-cell transformation and exerts transcriptional control of HLA disease-risk alleles associated with MS and other autoimmune disorders; 2. the EBV lytic protein, BZLF2, which also interacts with MHC2 and may influence the immunopathogenesis of MS; 3. the latency protein LMP1 that increases expression of proinflammatory cytokines; 7. exosomes released from EBV-infected B cells in the brain containing viral miRNAs, viral transactivators, and inflammatory cytokines that may contribute to virus mediated damage in the CNS; and 8. EBERs that may contribute directly to the inflammatory milieu of the MS lesion by inducing IFN-a and other components of the innate immune system. Host determinants involved in EBV-associated CNS damage may include: 2. Susceptible HLA alleles; 3. Poor CTL control of EBV infection that results in the persistence of inflammatory B cells with increased trafficking to the CNS; 4. molecular mimicry and 5. bystander damage that results from T cell targeting of EBV infection in the CNS and 6. damage from inflammatory B cells present in the brain