Collections > Electronic Theses and Dissertations > Manipulation and Exploitation of the Host Cell by Kaposi's Sarcoma-Associated Herpesvirus
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Kaposi’s sarcoma-associated herpesvirus (KSHV) is a human gamma-herpesvirus that is the causative agent of three human malignancies: Kaposi’s sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease. KSHV causes a lifelong infection for which there is no known cure, and the cancers associated with KSHV typically have poor prognosis and no established treatment protocol. KSHV is a large DNA virus that encodes over eighty open reading frames that have diverse functions, including viral proteins that thwart the host immune system and that alter cellular growth pathways to promote viral persistence, with the incidental effect of inducing cellular transformation. KSHV expresses several homologs of human proteins, including a homolog of interleukin 6 (hIL-6) called viral interleukin 6 (vIL-6). vIL-6 is a predominantly intracellular protein that localizes to the endoplasmic reticulum where it can signal through the gp130 subunit of the IL-6 receptor. We sought to examine how vIL-6 interacts with components of the host cell and alters host gene expression to promote vIL-6 function and induce pathogenesis. We identified hypoxia upregulated protein 1 (HYOU1) as a vIL-6-interacting partner, and found that HYOU1 supports vIL-6 protein expression and promotes vIL-6-mediated signaling, migration, and survival in endothelial cells. We also found that vIL-6 significantly upregulates the expression of genes associated with cellular movement including the adhesion factor called carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). We determined that vIL-6 increases CEACAM1 expression via STAT3 signaling, and that CEACAM1 promotes vIL-6-mediated migration of endothelial cells. Both de novo and latent KSHV infection were also found to upregulate CEACAM1. To further elucidate how KSHV modulates the cellular environment, we performed kinome profiling to identify cellular kinases that are differentially activated during latent and lytic KSHV infection in primary effusion lymphoma. Kinases regulate almost all cellular processes, and dysregulated kinase activation can drive tumorigenesis. This research may identify major pathogenic signaling pathways that are hyperactivated or shut off in KSHV-associated cancers. Further elucidating how KSHV and its encoded proteins alter the cellular environment to promote pathogenesis will identify targets for the development of novel therapeutics to treat KSHV-associated disease.