Dissertation
Regulating immunity via exosomes by the retroviral bZip protein, HBZ, in HTLV-1-induced neuroinflammation
Doctor of Philosophy (Ph.D.), Drexel University
May 2024
DOI:
https://doi.org/10.17918/00010446
Abstract
HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive neuroinflammatory demyelinating condition of the spinal cord. Aberrant expression and activity of immune checkpoint (ICP) molecules such as PD-1 and PD-L1/2, negatively associates with the cytolytic potential of T cells in individuals with HAM/TSP. Interestingly, ICPs can exist in a soluble cell-free form and can be carried on extracellular vesicles (EVs) and exosomes (small EVs, <200nm) while maintaining their immunomodulatory activity. Therefore, we investigated the role of soluble and exosomal ICPs in HTLV-1 associated neuroinflammation. For the first time, we demonstrate unique elevated presence of several stimulatory (CD27, CD28, 4-1BB) and inhibitory (BTLA, CTLA-4, LAG-3, PD-1, PD-L2) ICP receptors in HAM/TSP sera, and in purified exosomes from a HAM/TSP-derived HTLV-1-producing (OSP2) cells. These ICPs were found to be co-localized with the endosomal sorting complex required for transport (ESCRT) pathway proteins and exhibited functional binding with their respective ligands. Viral proteins and cytokines (primarily IFNγ) were found to be present in purified exosomes. IFNγ exposure boosted release of ICP molecules while antiretroviral drugs (Azidothymidine and Lopinavir) significantly inhibited this process. Moreso, exosomes from OSP2 cells induced proinflammatory cytokine responses in Dendritic cells and polarized CD4+ T-helper cells towards Th1/Treg phenotypes, while adversely effected CD8 T-cell functions with reduced levels of cytotoxic factors. HTLV-1 b-Zip protein (HBZ) has been linked to factors that enhance EV release and its knockdown led to the reduced expression of TrkB and ESCRT genes as well as abrogated release of ICP molecules, suggesting HBZ involvement in this process. In a CREB dependent manner, TrkB was seen to be enriched in at an ISRE promotor which is known to enhance PD-L2 and BTLA expression. Collectively, our studies show one potential mechanism in which HBZ modulates exosomal ICP release and the impact exosomes have in immunopathology.
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Details
- Title
- Regulating immunity via exosomes by the retroviral bZip protein, HBZ, in HTLV-1-induced neuroinflammation
- Creators
- Julie Joseph
- Contributors
- Pooja Jain (Advisor) - Drexel University, Neurobiology and Anatomy
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xiii, 164 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Microbiology and Immunology; College of Medicine; Drexel University
- Other Identifier
- 991021874915604721