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    Viral and Host Factor Interactions in the Regulation of JC Virus Reactivation

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    Genre
    Thesis/Dissertation
    Date
    2018
    Author
    Craigie, Michael John
    Advisor
    Sariyer, Ilker K.
    Committee member
    Fischer-Smith, Tracy
    Gordon, Jennifer
    Khalili, Kamel, 1951-
    Nonnemacher, Michael R.
    Department
    Infectious Disease & Immunity
    Subject
    Neurosciences
    Permanent link to this record
    http://hdl.handle.net/20.500.12613/2729
    
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    DOI
    http://dx.doi.org/10.34944/dspace/2711
    Abstract
    JC virus (JCV) is a human neurotropic polyomavirus and the etiologic agent of progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the white matter. PML is primarily observed in immunocompromised patients, including patients with acquired immunodeficiency syndrome (AIDS) and those prescribed immunomodulatory therapies. During JCV infection, the virus encodes multiple viral proteins including T-antigen and agnoprotein. Originally, we demonstrated that T-antigen expression rescued serine/arginine rich splicing factor 1 (SRSF1)-mediated transcriptional suppression of JCV for both early and late promoter orientations. We demonstrated that T-antigen expression suppressed SRSF1 expression in glial cells through inhibition of SRSF1 transcription. We have recently shown that agnoprotein is secreted from transfected cells into the extracellular matrix, where it is internalized by neighboring uninfected astrocytes or microglia. The internalization of agnoprotein was found to impact astrocyte’s cytokine profile, with treatment of astrocytes with media containing agnoprotein resulting in a significant reduction in granulocyte-macrophage colony-stimulating factor (GM-CSF) secretion. Subsequent reporter gene analysis demonstrated that agnoprotein can suppress GM-CSF transcription, implicating a possible mechanism for the reduction of GM-CSF secretion. Likewise, the treatment of a human monocyte cell line, U-937, with agnoprotein resulted in decreased differentiation, dysregulated surface marker expression, and decreased phagocytic ability. Similarly, treatment of peripheral blood mononuclear cells with agnoprotein decreased cellular migration through an in vitro blood brain barrier model. These findings have suggested that extracellular agnoprotein modulates aspects of the immune response to JCV, primarily through suppression of GM-CSF secretion and a subsequent dysregulation on monocyte/macrophage function.
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