Modulating the local innate immune response in the central nervous system to protect against progressive multifocal leukoencephalopathy

Gamble, Alistair James (2024) Modulating the local innate immune response in the central nervous system to protect against progressive multifocal leukoencephalopathy. PhD thesis, University of Glasgow.

Abstract

Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterised by inflammation and demyelination. As a leading cause of disability in adults, several disease modifying therapies are now available. Many of these work by suppressing the immune system which, while effective, can leave people with MS susceptible to opportunistic infections. One of the most severe of these is progressive multifocal leukoencephalopathy (PML), a rare but often fatal infection of oligodendrocytes by Human Polyomavirus 2, more commonly known as John Cunningham virus. There currently are no antivirals or vaccines for PML, therefore the only treatment option involves stopping immunosuppressive treatments, leaving patients at risk of further MS-related inflammatory events. As a result, there is a need to develop antivirals that work in conjunction with immunosuppressive treatments.
A subset of MS patients synthesise intrathecal lipid-reactive IgM, the presence of which has been associated with a reduced incidence of PML. This is compatible with our lab’s recent observation that the murine lipid-reactive IgM antibody clone O4, when added to murine myelinating cell cultures, induces the expression of interferon beta (IFN-β). As IFN-β is produced in response to viral infection, these data could explain why individuals with lipid-reactive IgM seem protected from PML.
These findings prompted our investigation into the effect of IFN-β treatment on the major cell types of the CNS; the oligodendrocytes, microglia, neurons, and astrocytes. Using murine CNS cell cultures, we utilised fluorescence activated cell sorting (FACS) to separate out the individual cell types of the CNS for RNAseq analysis. This way we characterised the unique transcriptional profile of each individual cell-type following IFN-β treatment. Importantly, several oligodendrocyte-unique genes were upregulated including Il10ra, the gene encoding IL-10R. It was deduced through RT-qPCR, plaque assays, and fluorescence microscopy that treatment with IFN-β or blocking IL-10R was able to decrease infectivity of a model neurotropic virus both in vitro and in vivo.
The data presented in this thesis provides evidence of innate antiviral activity of oligodendrocytes which can be manipulated pharmacologically to protect against viral infection. This research will aid in the development of future therapeutics to decrease the infectivity of JCV in the CNS. This would allow MS patients to remain on their effective therapeutics without being at increased risk. Further investigation of the IFN-β response of the CNS could lead to the development of an antiviral therapy that can be used as a cotreatment in MS or as a broad-spectrum antiviral for viral encephalitis.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Supported in part by the MS Society, and by extension the Lorna and Yuti Chernajovsky Foundation.
• Subjects: Q Science > QR Microbiology > QR180 Immunology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Supervisor's Name: Pingen, Dr. Marieke and Edgar, Professor Julia
• Date of Award: 2024
• Depositing User: Theses Team
• Unique ID: glathesis:2024-84201
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 03 Apr 2024 14:12
• Last Modified: 25 Feb 2026 16:33
• Thesis DOI: 10.5525/gla.thesis.84201
• URI: https://theses.gla.ac.uk/id/eprint/84201

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