Date of Award
Doctor of Philosophy (PhD)
Plasmacytoid dendritic cells (pDC) are a specialized group of circulating dendritic cells that respond to viral nucleic acids with Type I IFN production as well as other cytokine and chemokines. These pDC responses lead to the production of antiviral molecules and recruitment of defense cells. During zoonotic B virus infection, a simplex virus of the subfamily Alphaherpesviridae, our lab has observed that infected individuals who succumb to infection have little-to-no-antibody or cell-mediated defenses. To identify whether this was partly due to failure of pDCs to produce antiviral interferon responses or produce chemokine and cytokines, we tested the hypothesis that B virus modulates the IFN response during zoonotic infection by blocking pDC activation and subsequent IFN signaling pathways to circumvent host defenses, while these pathways remain intact in the macaque hosts. We showed that human pDCs respond to B virus through the production of IFN-a, IL-1a, IL-6, TNF-a, MIP-1a/b and IP-10. Human pDCs co-cultured with B virus infected fibroblasts produced fewer cytokines and at lower levels. The macaque response to B virus was measured using PBMCs, as there are no specific reagents available to enrich macaque pDCs. Human and macaque PBMCs produced IFN-a when exposed directly to B virus infected lysates. Co-cultures of PBMCs with B virus infected fibroblasts from both hosts failed to produce any significant amounts of IFN-a. To quantify the antiviral effects of PBMC induced IFN-a, we measured B virus titers after exposure to supernatants from B virus exposed PBMCs, PBMC co-cultures with infected fibroblasts and exogenous recombinant Type I IFN. Our data further suggest that B virus resistance was not due to virus specific blockade of the Type I IFN signaling pathway because STAT-1 was activated in infected fibroblasts when treated with Type I IFNs. These data demonstrate for the first time that B virus replication is unimpeded in the presence of any source of IFN-a in either host cell type. In conclusion, this dissertation shows that the IFN-a production by both hosts in response to B virus is similar and that IFN-a treatment of B virus infected fibroblasts did not reduce B virus replication.
Brock, Nicole, "Host-specific Plasmacytoid Dendritic Cell Defenses In The Presence of Human and Macaque Skin Cells Infected with B virus." Dissertation, Georgia State University, 2014.
Available for download on Friday, April 24, 2015