Activation of MSRV-type endogenous retroviruses during infectious mononucleosis and Epstein-Barr virus latency: the
Giuseppe Mameli1, Giordano Madeddu, Alessandra Mei
1Department of Biomedical Sciences, University of Sassari, Sassari, Italy.
Abstract:
The etiology of multiple sclerosis (MS) is still unclear. The immuno-pathogenic phenomena leading to neurodegeneration are thought to be triggered by environmental (viral?) factors operating on predisposing genetic backgrounds. Among the proposed co-factors are the Epstein Barr virus (EBV), and the potentially neuropathogenic HERV-W/MSRV/Syncytin-1 endogenous retroviruses. The ascertained links between EBV and MS are history of late primary infection, possibly leading to infectious mononucleosis (IM), and high titers of pre-onset IgG against EBV nuclear antigens (anti-EBNA IgG). During MS, there is no evidence of MS-specific EBV expression, while a continuous expression of HERV-Ws occurs, paralleling disease behaviour. We found repeatedly extracellular HERV-W/MSRV and MSRV-specific mRNA sequences in MS patients (in blood, spinal fluid, and brain samples), and MRSV presence/load strikingly paralleled MS stages and active/remission phases. Aim of the study was to verify whether HERV-W might be activated in vivo, in hospitalized young adults with IM symptoms, that were analyzed with respect to expression of HERV-W/MSRV transcripts and proteins. Healthy controls were either EBV-negative or latently EBV-infected with/without high titers of anti-EBNA-1 IgG. The results show that activation of HERV-W/MSRV occurs in blood mononuclear cells of IM patients (2Log10 increase of MSRV-type env mRNA accumulation with respect to EBV-negative controls). When healthy controls are stratified for previous EBV infection (high and low, or no anti-EBNA-1 IgG titers), a direct correlation occurs with MSRV mRNA accumulation. Flow cytometry data show increased percentages of cells exposing surface HERV-Wenv protein, that occur differently in specific cell subsets, and in acute disease and past infection. Thus, the data indicate that the two main links between EBV and MS (IM and high anti-EBNA-1-IgG titers) are paralleled by activation of the potentially neuropathogenic HERV-W/MSRV. These novel findings suggest HERV-W/MSRV activation as the missing link between EBV and MS, and may open new avenues of intervention.
Insights
Epstein Barr virus (EBV) infection, particularly infectious mononucleosis (IM), correlates with Human Endogenous Retrovirus W (HERV-W) activation. This activation may be the missing link connecting EBV to multiple sclerosis (MS) pathogenesis.
Area of Science:
- Neuroimmunology
- Virology
- Genetics
Background:
- The etiology of multiple sclerosis (MS) remains unclear, with environmental factors and genetic predisposition implicated.
- Epstein Barr virus (EBV) and Human Endogenous Retroviruses (HERV-W) are proposed co-factors in MS pathogenesis.
- Previous research noted links between EBV infection (infectious mononucleosis, IM) and high anti-EBNA IgG titers with MS, alongside continuous HERV-W expression in MS patients.
Purpose of the Study:
- To investigate in vivo activation of HERV-W/MSRV in young adults with infectious mononucleosis (IM) symptoms.
- To determine the correlation between EBV infection status and HERV-W/MSRV activation.
- To explore the potential role of HERV-W/MSRV activation as a link between EBV and MS.
Main Methods:
- Analysis of HERV-W/MSRV transcripts and proteins in blood mononuclear cells of IM patients and healthy controls.
- Stratification of healthy controls based on EBV infection status (EBV-negative, latent EBV infection with varying anti-EBNA-1 IgG titers).
- Flow cytometry to assess cell surface HERV-Wenv protein expression.
Main Results:
- Significant activation of HERV-W/MSRV was observed in IM patients, with a 2Log10 increase in MSRV-type env mRNA.
- A direct correlation between prior EBV infection (indicated by anti-EBNA-1 IgG titers) and MSRV mRNA accumulation was found in healthy controls.
- Increased percentages of cells expressing surface HERV-Wenv protein were detected in IM patients and individuals with past EBV infection.
Conclusions:
- HERV-W/MSRV activation occurs in vivo during infectious mononucleosis and correlates with EBV infection history.
- These findings suggest HERV-W/MSRV activation serves as a potential link between EBV and the development of multiple sclerosis.
- The study opens new avenues for therapeutic interventions targeting HERV-W in MS.
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