DEFINING THE ROLE OF IP3R-MEDICATED ER CALCIUM FLUX IN JC POLYOMAVIRUS INFECTION
Author: Ashley N. Soucy
Graduation Year: 2018
Thesis Advisor: Melissa Maginnis
Description of Publication: The human JC polyomavirus (JCPyV) persists as an asymptomatic infection in the kidneys of healthy individuals within the majority of the global population. Viral infection of JCPyV is established through peroral transmission due to poor sanitary practices. In severely immunocompromised individuals, JCPyV migrates to the central nervous system (CNS), resulting in the fatal and incurable demyelinating disease progressive multifocal leukoencephalopathy (PML). Virus-host cell interactions regulate infectious processes and influence viral pathogenesis. JCPyV attachment to host cells is mediated by α2,6-linked LSTc while internalization is mediated by 5-hydroxytryptamine serotonin type 2 receptors (5-HT2Rs). Activation of 5-HT2Rs can induce intracellular calcium (Ca2+) release upon ligand binding to activate the inositol triphosphate receptor (IP3R) signaling pathways. The goal of this project was to determine the role of intracellular Ca2+ flux in JCPyV infection. JCPyV induces Ca2+ flux from the ER almost immediately upon infection. Limiting Ca2+ release from the ER by inhibition of the IP3R with chemical antagonists significantly reduced JCPyV infection in both human kidney and brain cells, demonstrating a dependence on Ca2+ flux to regulate JCPyV infection. Although, JCPyV-induced Ca2+ flux occurs at times consistent with viral attachment and entry, analyses of these steps by flow cytometric assays, revealed that JCPyV attachment and entry were not affected by modulation of Ca2+ flux. These findings demonstrate that Ca2+ flux is regulated upon JCPyV infection and provide important insights into the activation of signaling pathways to drive the infectious process. In the future, this work can increase our understanding of PML pathogenesis and aid in the development of novel PML therapeutics.
Location of Publication:
URL to Thesis: https://digitalcommons.library.umaine.edu/honors/354