Date of Award

Spring 1-1-2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Robert L. Garcea

Second Advisor

Leslie Leinwand

Third Advisor

Gia Voeltz

Fourth Advisor

Sara Sawyer

Fifth Advisor

Natalie Ahn

Abstract

Virus binding to the cell surface triggers an array of host responses important for infection. Gangliosides are the cell surface receptors for Polyomavirus (PyV) infection. Specificity is determined by recognition of carbohydrate moieties on the ganglioside by the major viral capsid protein VP1 and alterations in ganglioside binding cause dramatic changes in virus tropism and pathogenesis. Knockout mice lacking complex gangliosides are completely resistant to Mouse Polyomavirus (MuPyV) infection. Fibroblasts (MEFs) from these mice are likewise resistant to infection, and supplementation with specific gangliosides: GD1a, GT1b, and GT1a rescues infection. MuPyV also binds a protein receptor α4-integrin and loss of integrin binding results in a 60% decrease in infection. In the absence of these receptors MuPyV binds and enter cells, thus how glycan receptors mediate infectious entry is unclear. Using mutant viruses and cell lines we determined that gangliosides and α4-integrin receptors mediate MuPyV activation of specific host signaling pathways. Using small molecule inhibitors, we identified that the PI3K and FAK/SRC pathways were required for MuPyV infection. The PI3K pathway was required for MuPyV endocytosis, while the FAK/SRC pathway enabled trafficking of MuPyV along microtubules. Thus, MuPyV interactions with specific cell surface receptors facilitate activation of signaling pathways required for virus entry and trafficking. Understanding how different viruses manipulate cell-signaling pathways though interactions with host receptors could lead to the identification of new therapeutic targets for viral infection.

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