Date of Award
Doctor of Philosophy (PhD)
Dr. Jennifer Totonchy
Dr. Rennolds Ostrom
Dr. Sun Yang
Dr. Ajay Sharma
Despite nearly three decades of research, not much is known regarding the early stages of development for KSHV lymphoproliferative disorders, hindering our ability to develop prophylactic measures or effective treatments. This dissertation will focus on the host and viral factors influencing the magnitude and dynamics of KSHV infection in the human tonsil to pave the way for future interventions directed at limiting person-to-person transmission of KSHV.
To understand the contribution of host factors to KSHV susceptibility in B lymphocytes, we generated a library of 40 tonsillar specimens. Our results indicate that the immunological composition of tonsillar lymphocytes varies across our donor samples, and KSHV possess a diverse B lymphocyte tropism. Furthermore, the highly specific targeting of plasma cells is not due to CD138 (Syndecan-1) being used as an attachment factor, and heparan sulfates, in general, do not play an important role in KSHV infection of B cells. Finally, the donor-dependent immunological factors and immune status of individual samples influences the overall susceptibility, as well as specific targeting of B cell lineages.
To understand the significance of viral gH/gL glycoprotein interaction with some of the key EphA family of receptors in the process of KSHV entry into B lymphocytes, we demonstrate that the expression of EphA2, EphA4, and EphA7 are donor and subset-specific and gH/gL-EphA interactions are important for KSHV-WT infection of primary tonsil lymphocytes. These interactions are critical for establishing KSHV-WT infection of plasma cells and germinal center cells, and KSHV exploits alternative mechanism of entry in absence of gH.
Finally, we develop a model for cell-to-cell transmission of KSHV within human tonsils by examining KSHV spread within and between primary cell types derived from tonsil specimens, located at the proximity of the crypt lumen, which are in direct contact with external pathogens present in saliva. We show that a variety of primary tonsillar cells are susceptible to KSHV infection and can differentially transmit the infection into B cells. We demonstrate that KSHV spread between and within tonsil cell types is directed, suggesting, this tropism may be influenced by differential virion composition arising from each cell type.
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Aalam, F. KSHV Susceptibility and Transmission Within Tonsillar Specimens. [dissertation]. Irvine, CA: Chapman University; 2021. https://doi.org/10.36837/chapman.000325