Grant: Project Grant

Pathogenic RNA viruses of the Flaviviridae family include Zika (ZIKV), West Nile (WNV), Dengue (DV), and Hepatitis C (HCV). ZIKV outbreaks are occurring in more than 80 countries and in 2016 the World Health Organization (WHO) declared a Public Health Emergency of International Concern. DV is endemic in at least 100 countries and WHO estimates that nearly 400 million infections occur yearly, while HCV causes serious liver damage with more than 170 million individuals infected worldwide. A central tenant of Flaviviridae virus biology, and one that guides therapeutic strategies, is that the virus production cycle occurs within the cytoplasm of host cells. However, we recently discovered that the RNA genomes of ZIKV and HCV shuttle in and out of the host cell nucleus. The movement of ZIKV and HCV RNA genomes through the host nucleus has not been explored in the literature, and the functional importance of nuclear viral RNAs remains completely unknown. Critically, altering the transport of ZIKV and HCV RNAs through the nucleus negatively impacts virus production, pointing to a crucial, yet uncharacterized, role for the nucleus in Flaviviridae biology. We hypothesize that the vRNA genomes of ZIKV and HCV enter the host nucleus to (1) engage nuclear pathways that aid in virus production and (2) to regulate host cell gene expression including activition of cell defence mechanisms. We expect that our research will produce new knowledge, technologies, and methodologies that will establish an area of research with pan-Flaviviridae therapeutic opportunities.