Type I interferons (IFNs) are well-characterized cytokines that inhibit a wide range of viruses. The cellular proteins that mediate the antiviral functions of IFN are derived from interferon-stimulated genes (ISGs), and are potentially exploitable for the development of pan-tropic antiviral drugs. Unfortunately, very little is known about which ISGs are antiviral, their specificity is largely undetermined, and their mechanisms of action remain elusive. We propose to address this gap in scientific knowledge by conducting a series of large-scale screens to determine the """"""""ISG profile"""""""" of diverse viruses. We have cloned over 380 commonly upregulated ISGs into a lentiviral vector and optimized conditions to correlate the expression of these genes with viral replication using a two-color flow cytometric assay. The ISG library will be used to probe ISG antiviral function against an array of viruses form diverse families, with a special emphasis on hepatitis C virus (HCV) and influenza virus A (FluA). Each of these viruses has a significant impact on global health, with pathologies ranging from hepatocellular carcinoma to severe respiratory disease, and potential outcomes spanning life-long chronic infection to acute pandemic events. Comparison of ISG profiles from across viral species, genera, and families will begin to reveal the range of ISG specificities. Screens of select viruses under different cellular conditions will address the depth of ISG function. Validation and mechanistic dissection of the most interesting hits will clarify the roles of ISGs in combating infection, and may yield new strategies for translating naturally occurring broad-spectrum antiviral activities into clinically useful compounds.
Hepatitis C, influenza A, and other infectious diseases cause nearly 15 million deaths each year. Therapeutic options for viral infections are often severely limited. Here we propose to investigate the activity of cellular interferon-stimulated genes (ISGs) against diverse viruses in the hopes of identifying candidates to guide development of broad-spectrum antiviral drugs.
|Wu, Xianfang; Dao Thi, Viet Loan; Huang, Yumin et al. (2017) Intrinsic Immunity Shapes Viral Resistance of Stem Cells. Cell :|
|Mendoza, Juan L; Schneider, William M; Hoffmann, Hans-Heinrich et al. (2017) The IFN-?-IFN-?R1-IL-10R? Complex Reveals Structural Features Underlying Type III IFN Functional Plasticity. Immunity 46:379-392|
|Michailidis, Eleftherios; Pabon, Jonathan; Xiang, Kuanhui et al. (2017) A robust cell culture system supporting the complete life cycle of hepatitis B virus. Sci Rep 7:16616|
|Li, Melody M H; Lau, Zerlina; Cheung, Pamela et al. (2017) TRIM25 Enhances the Antiviral Action of Zinc-Finger Antiviral Protein (ZAP). PLoS Pathog 13:e1006145|
|Rosenberg, Brad R; Freije, Catherine A; Imanaka, Naoko et al. (2017) Genetic variation at IFNL4 influences extrahepatic interferon stimulated gene expression in chronic HCV patients. J Infect Dis :|
|Luna, Joseph M; Wu, Xianfang; Rice, Charles M (2016) Present and not reporting for duty: dsRNAi in mammalian cells. EMBO J 35:2499-2501|
|Scheel, Troels K H; Luna, Joseph M; Liniger, Matthias et al. (2016) A Broad RNA Virus Survey Reveals Both miRNA Dependence and Functional Sequestration. Cell Host Microbe 19:409-23|
|Li, Melody M H; Bozzacco, Leonia; Hoffmann, Hans-Heinrich et al. (2016) Interferon regulatory factor 2 protects mice from lethal viral neuroinvasion. J Exp Med 213:2931-2947|
|Yao, Hui; Dittmann, Meike; Peisley, Alys et al. (2015) ATP-dependent effector-like functions of RIG-I-like receptors. Mol Cell 58:541-548|
|Hoffmann, Franziska S; Schmidt, Andreas; Dittmann Chevillotte, Meike et al. (2015) Polymorphisms in melanoma differentiation-associated gene 5 link protein function to clearance of hepatitis C virus. Hepatology 61:460-70|
Showing the most recent 10 out of 30 publications