DoctorBunny…Is EBV the target in MS?


ProfG has gone off into the sunset to prevent MS and getting rid of Epstein Barr Virus would be one of his favourite approaches. One could test out the approach in MS, but probably it is a bit late for that or maybe in a few school children, but how about animal models. We have said that EBV doesn’t really infect animals. I know this is not quite true as you can get non-human primates infected and humanised mice can be used where you fill a moose full of human cells, but here you can apparently use Bunnies.

Hassani A, Reguraman N, Shehab S, Khan G. Primary Peripheral Epstein-Barr Virus Infection Can Lead to CNS Infection and Neuroinflammation in a Rabbit Model: Implications for Multiple Sclerosis Pathogenesis. Front Immunol. 2021;12:764937. doi: 10.3389/fimmu.2021.764937. 

Epstein-Barr virus (EBV) is a common herpesvirus associated with malignant and non-malignant conditions. An accumulating body of evidence supports a role for EBV in the pathogenesis of multiple sclerosis (MS), a demyelinating disease of the CNS. However, little is known about the details of the link between EBV and MS. One obstacle which has hindered research in this area has been the lack of a suitable animal model recapitulating natural infection in humans. We have recently shown that healthy rabbits are susceptible to EBV infection, and viral persistence in these animals mimics latent infection in humans. We used the rabbit model to investigate if peripheral EBV infection can lead to infection of the CNS and its potential consequences. We injected EBV intravenously in one group of animals, and phosphate-buffered saline (PBS) in another, with and without immunosuppression. Histopathological changes and viral dynamics were examined in peripheral blood, spleen, brain, and spinal cord, using a range of molecular and histopathology techniques. Our investigations uncovered important findings that could not be previously addressed. We showed that primary peripheral EBV infection can lead to the virus traversing the CNS. Cell associated, but not free virus in the plasma, correlated with CNS infection. The infected cells within the brain were found to be B-lymphocytes. Most notably, animals injected with EBV, but not PBS, developed inflammatory cellular aggregates in the CNS. The incidence of these aggregates increased in the immunosuppressed animals. The cellular aggregates contained compact clusters of macrophages surrounded by reactive astrocytes and dispersed B and T lymphocytes, but not myelinated nerve fibers. Moreover, studying EBV infection over a span of 28 days, revealed that the peak point for viral load in the periphery and CNS coincides with increased occurrence of cellular aggregates in the brain. Finally, peripheral EBV infection triggered temporal changes in the expression of latent viral transcripts and cytokines in the brain. The present study provides the first direct in vivo evidence for the role of peripheral EBV infection in CNS pathology, and highlights a unique model to dissect viral mechanisms contributing to the development of MS

Upon primary infection, rabbits elicited a strong humoral response, correlating with undetectable levels of the virus in peripheral blood. However, immunosuppression of latently infected animals using cyclosporin A (CsA), resulted in reactivation and marked increase in peripheral viral load. EBV reactivation was associated with the expression of the immediate early lytic marker, BZLF1, and a handful of latent viral genes. These animals also showed pronounced infiltration of infected cells into the liver and the spleen.

So interesting but I wonder if this is the link of EBV to MS

Am I going to get a new persona

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  • “The infected cells within the brain were found to be B-lymphocytes.”

    How come T-Cell only blockers work on reducing ARR?

    • T cell only blockers…..What do you think they are?.

      There is no such thing (T cell only blocker) in use in MS and from what I have read T cell only agents dont work very well?….Eg. Anti CD4. For example Natalizumab = T cells, B cells monocytes

  • Interesting! Thank you for posting. As one who has had chronic reactivating EBV driving progression, it’s good to see research in this area. Happily, I’m finally off 3 years of antivirals after year 2 Mavenclad.

  • Although the rabbit model is NOT a model of MS, but rather a model of EBV infection, this study has revealed a number of pertinent questions related to the role of EBV in the pathogenesis of MS.

    • Peripheral EBV infection can lead to the virus infecting the brain.
    • EBV appears to enter the brain via infected B-cells rather than free virus – ‘Trojan Horse mechanism’.
    • EBV infection of the brain can result in neuroinflammation, with the appearance of distinct inflammatory cellular aggregates.
    • Inflammatory aggregates consist of macrophages, surrounded by lymphocytes, and reactive astrocytes, but absence myelinated fibres
    • The expression of EBV latent transcripts is associated with the upregulation of proinflammatory cytokines.

    We believe this EBV rabbit model could help in further dissecting the role of EBV in the pathogenesis of MS.

  • Oh, what a surprise! NOT. Another bit of research showing what we all expect, while the majority of sheep/neuros cling on to outdated, incorrect concepts of autoimmunity. What will it take to make them see the light? A randomised, double blind, placebo controlled, intervention study where a few million babies are infected with a strain of EBV from a patient with severe PPMS and then monitored to see when they develop MS? If they argue that it would be unethical, they must accept that EBV is not the benign, inconsequential vector that they purport it to be.

    • ‘intervention study where a few million babies are infected with a strain of EBV from a patient with severe PPMS’

      Do this an MS may not develop, infection at a young age may keep MS from developing.

      Just a theory

      • If it were shown to be protective, it would be a monumental win. It would provide an end to MS for future generations.

    • Although we can’t do randomised, double blind, placebo controlled trial on a few million kids, we can on a group of rabbits!

      We are in fact planning to examine if the neuropathology seen in the rabbit brain following EBV infection can be ameliorated by targetting the B-cells that the virus normally infects using rituximab. We hope this ‘Koch Postulate’ approach, if it works, will convince the skeptics. If we had an effective vaccine against EBV, that would have made life much simpler in addressing the causal relationship.

  • No b cell present in very early ms lesions

    Myelin breakdown is initiated by a population of IgGpositive
    macrophages contacting largely intact myelin sheaths
    that stain positively for activated complement (C9neo). The
    appearance of this population occurs in the presence of a disrupted
    blood-brain barrier and is associated closely with commencing
    recruitment into the tissue of IgG-positive blood
    monocytes. Microglia and early activated microglia, in the absence
    of recruited monocytes, are nonphagocytic. How monocytes
    combine with nonphagocytic microglia to generate a
    population of phagocytes is unclear. The result, however, is
    the abrupt appearance in tissue that normally has no IgG and
    no Fc receptor-bearing cells of a large apparently homogeneous
    population of IgG-positive Fc receptor-bearing phagocytes
    that target myelin sheaths, apoptotic oligodendrocytes
    and astrocytes but leave nerve cells and axons relatively untouched.
    It is unclear how much of this macrophage activity is
    mediated by innate and adaptive immune mechanisms.

    doi: 10.1093/jnen/nlab083

    Nice work

  • Love this concept, good basis for drug testing and an animal anti viral study. But whatever you do please do not become BunnyDoctor!!

  • Long list of ebv MS references… including a couple of famous names. Am always amazed by quite how much MS research is out there, most of which is never heard of again.

    Made me think, warning completely off topic: When I was at uni decades ago, there was no PubMed or even Medline (for lowly undergrads), researching a project was an art form involving physical search through shelf loads of journals followed by racking up a small fortune on photocopy account. Used to take days. No internet, no research blogs, no Twitter, amazing we learnt anything really!

    • We built a mountain of photo copies for our research. Looking back, expanding our knowledge was not good for the environment🙂

    • PubMed appeared in 1997 a few years before I finished Uni. Before that we were expected to access citations by searching libraries or electronically through a dedicated program – I forget what it was called, but the command line syntax for searches was bewilderingly complicated. PubMed transformed researching an essay and reduced rain forest destruction. Although, we still had to print numerous copies of the essays and Turnitin didn’t exist.

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