Identification and characterization of the antiviral mode of action of interferon-stimulated genes

• Applicant: Professorin Dr. Meike Dittmann
• Subject Area: Virology
• Term: from 2012 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 226487190

Type-I interferons (IFNs) are major innate immune messengers that are produced by cells upon viral infection. They trigger transcriptional upregulation of a subset of host genes called interferon stimulated genes (ISGs). The concert of hundreds of expressed ISGs builds a robust line of defense. IFNs are used therapeutically but cause severe side effects. A better understanding of the multi-layered ISG barrier is crucial to allow manipulation of ISG effector function in a more targeted manner. Currently, several hundred ISGs remain largely uncharacterized. Previous studies that aimed to identify antiviral ISG effectors have focused predominantly on early stages of viral infection. As a result, a potential pool of antiviral ISGs that inhibit late stages of virus infection (assembly, egress or particle infectivity) has yet to be identified. I propose a project to investigate ISG effector functions. First, I will characterize the antiviral function of the ISG DDX60, recently shown to inhibit hepatitis C virus (HCV). Based on sequence homology to proteins with known function, I hypothesize that DDX60 might inhibit viral protein translation or undermine viral RNA stability. I propose to perform a number of functional assays, including mapping of functional motifs and viral life cycle studies in order to define the mechanism by which DDX60 inhibits HCV. Second, I plan to identify ISGs that specifically inhibit late stages in virus lifecycles. I will modify a current ISG gain-of-function assay and utilize the 300+ ISGs from a previously published ISG screen to identify inhibitors of influenza A virus, HCV, West Nile virus, Dengue virus, and yellow fever virus. I expect that the results from this screen will enable side-by-side comparison of ISGs that inhibit late lifecycle stages of each of these viruses, providing insight into similarities and differences in viral egress mechanisms.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Charles M. Rice, Ph.D.