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. / Infectious Disease & Immunity
| Identifer | oai:union.ndltd.org:TEMPLE/oai:scholarshare.temple.edu:20.500.12613/2729 |
| Date | January 2018 |
| Creators | Craigie, Michael John |
| Contributors | Sariyer, Ilker K., Fischer-Smith, Tracy, Gordon, Jennifer, Khalili, Kamel, 1951-, Nonnemacher, Michael R. |
| Publisher | Temple University. Libraries |
| Source Sets | Temple University |
| Language | English |
| Detected Language | English |
| Type | Thesis/Dissertation, Text |
| Format | 183 pages |
| Rights | IN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available., http://rightsstatements.org/vocab/InC/1.0/ |
| Relation | http://dx.doi.org/10.34944/dspace/2711, Theses and Dissertations |
Page generated in 0.0017 seconds