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.
|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|
|Kane, Melissa; Zang, Trinity M; Rihn, Suzannah J et al. (2016) Identification of Interferon-Stimulated Genes with Antiretroviral Activity. Cell Host Microbe 20:392-405|
|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|
|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|
|Luna, Joseph M; Scheel, Troels K H; Danino, Tal et al. (2015) Hepatitis C virus RNA functionally sequesters miR-122. Cell 160:1099-110|
|Yao, Hui; Dittmann, Meike; Peisley, Alys et al. (2015) ATP-dependent effector-like functions of RIG-I-like receptors. Mol Cell 58:541-8|
|Li, Melody M H; MacDonald, Margaret R; Rice, Charles M (2015) To translate, or not to translate: viral and host mRNA regulation by interferon-stimulated genes. Trends Cell Biol 25:320-9|
|Dittmann, Meike; Hoffmann, Hans-Heinrich; Scull, Margaret A et al. (2015) A serpin shapes the extracellular environment to prevent influenza A virus maturation. Cell 160:631-43|
|Hoffmann, Hans-Heinrich; Schneider, William M; Rice, Charles M (2015) Interferons and viruses: an evolutionary arms race of molecular interactions. Trends Immunol 36:124-38|
|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|
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