The primary research goals of this Mentored Research Scientist Development Award proposal are to study the mechanisms by which types I and III interferon (IFN) cooperate to resolve hepatitis C virus (HCV) infection. Despite the ubiquitous use of IFN? for treatment of HCV infection, its mechanisms of action are poorly understood. The research plan is partly based on previous screening efforts by the candidate to identify and characterize type I IFN- stimulated genes (ISGs) with previously unknown antiviral activities. Additionally, with the recent discovery that genetic variation in IL28B (a type III IFN is associated with treatment-induced HCV clearance, new models have emerged suggesting a functional interdependence of these two IFN systems. The experimental aims are designed to test these models in the context of clinically- meaningful outcomes. The effects of IL28B genotype on IL28B production in IFN-treated peripheral blood mononuclear cells from HCV-infected patients will be determined. Next-generation sequencing of these samples will be used to correlate IL28B genotype to IFN?-induced changes in global gene expression. The functional interplay between these two IFN systems will be assessed in cell culture-based hepatocyte models of HCV infection, followed by next-generation transcriptome profiling. The gene profiling efforts will be used in combination with the candidate's prior ISG screens to pinpoint the strongest and/or most clinically relevant effectors for follow up antiviral mechanism of action studies in the independent phase. This research plan is intended to complement a comprehensive career development plan that includes mentorship in new areas related to deep sequencing technologies and translational research. The mentored phase of this award will be carried out in the laboratory or Dr. Charles Rice at The Rockefeller University, one of the world's leading virology laboratories and a source of significant resources and basic science expertise. As part of the Center for the Study of Hepatitis C, a joint venture with Weill Cornell Medical College and New York Presbyterian Hospital, this environment also offers access to a vibrant clinical and translational research community. Critical to the career development plan are attendance at professional conferences, regular meetings with an advisory committee, and courses that offer instruction in ethics, deep sequencing, and clinical/translational research techniques. Summarily, this training plan should satisfy the candidate's short-term goals of adding new technologies and approaches to an already extensive experimental repertoire, and long term goals of running an independent research program in molecular virology, virus-host cell interactions, and viral pathogenesis.
Hepatitis C virus (HCV) is the most common chronic blood-borne infection in the United States, with severe pathological sequelae including hepatitis, cirrhosis and hepatocellular carcinoma. HCV is not vaccine preventable and is frequently resistant to available therapies, which are based on interferon. A greater understanding of how interferon acts against HCV may lead to improved treatments for this and other viral infections.
|Mar, Katrina B; Rinkenberger, Nicholas R; Boys, Ian N et al. (2018) LY6E mediates an evolutionarily conserved enhancement of virus infection by targeting a late entry step. Nat Commun 9:3603|
|Rinkenberger, Nicholas; Schoggins, John W (2018) Mucolipin-2 Cation Channel Increases Trafficking Efficiency of Endocytosed Viruses. MBio 9:|
|Rosenberg, Brad R; Freije, Catherine A; Imanaka, Naoko et al. (2018) Genetic Variation at IFNL4 Influences Extrahepatic Interferon-Stimulated Gene Expression in Chronic HCV Patients. J Infect Dis 217:650-655|
|Richardson, R Blake; Ohlson, Maikke B; Eitson, Jennifer L et al. (2018) A CRISPR screen identifies IFI6 as an ER-resident interferon effector that blocks flavivirus replication. Nat Microbiol 3:1214-1223|
|Hanners, Natasha W; Eitson, Jennifer L; Usui, Noriyoshi et al. (2016) Western Zika Virus in Human Fetal Neural Progenitors Persists Long Term with Partial Cytopathic and Limited Immunogenic Effects. Cell Rep 15:2315-22|
|Schoggins, John W; MacDuff, Donna A; Imanaka, Naoko et al. (2015) Corrigendum: Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity. Nature 525:144|
|Feenstra, Bjarke; Pasternak, Björn; Geller, Frank et al. (2014) Common variants associated with general and MMR vaccine-related febrile seizures. Nat Genet 46:1274-82|
|Schoggins, John W (2014) Interferon-stimulated genes: roles in viral pathogenesis. Curr Opin Virol 6:40-6|
|Schoggins, John W; MacDuff, Donna A; Imanaka, Naoko et al. (2014) Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity. Nature 505:691-5|
|Kane, Melissa; Yadav, Shalini S; Bitzegeio, Julia et al. (2013) MX2 is an interferon-induced inhibitor of HIV-1 infection. Nature 502:563-6|
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