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Functional Genomic Dissection of Viral and Cellular Factors that Regulate JC Polyomavirus Infection

The goal of the Maginnis Laboratory is to define the cellular and molecular basis of viral disease. We study the human JC polyomavirus, which infects the majority of the population and causes the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML) in the brain of immunosuppressed individuals. Our research is focused on defining how the virus enters into host cells, traffics within the cell, and activates signaling cascades to cause infection. This research will enhance our understanding of how virus-host cell interactions influence disease outcomes and will serve as a platform for the development of treatments for PML.

Project Summary

JC polyomavirus (JCPyV) infects the majority of the human population and establishes a lifelong, asymptomatic infection in the kidney of healthy individuals. In immunocompromised individuals, JCPyV can spread to the central nervous system (CNS) and cause a lytic infection, resulting in the fatal, demyelinating disease progressive multifocal leukoencephalopathy (PML). The viral and cellular factors that contribute to JCPyV infection and PML pathogenesis remain poorly defined, and there are currently no effective treatments for this devastating disease. This research project will utilize comparative functional genomics to define virus-host cell interactions that regulate a persistent JCPyV infection in the kidney and cause a lytic, pathogenic infection in the brain. Targeted mutagenesis of the viral serotonin receptors together with siRNA screening and RNA sequencing will be used to define cellular endocytic factors that drive JCPyV internalization. To elucidate cellular signaling pathways that drive JCPyV infection, gene expression arrays and analysis of known signaling pathways will be explored to define how signaling events regulate viral internalization, trafficking, and transcription. A genome-wide siRNA screen and transcriptome profiling will be utilized to determine how alterations in gene expression and virus and cell-type dependent genomic differences influence JCPyV pathogenesis and fatal disease outcomes. This combinatorial approach takes advantage of both loss of function and gain of function genomic technologies to address key questions in JCPyV biology and the pathogenesis of the fatal disease PML. Information gained from this research will elucidate novel viral and cellular factors that could be targeted for the devleopment of effective antiviral therapies. Additionally, this research will contribute to a broader understanding of demyelinating disorders of the CNS, serotonin receptor biology, cell signaling events in viral pathogenesis, and cell-type dependent differences in human disease.

Relevance of Research

JC polyomavirus (JCPyV) is a significant human health problem as the virus resides in the kidney of the  majority of the population. The virus can become reactivated in immunosuppressed individuals and spreads to the brain, causing a fatal demyelinating disease known as progressive multifocal leukoencephalopathy (PML). There are currently very few treatment options for this rapidly-progressing and devastating disease.