Characterization of the mode of antiviral action of IRG 1

• Applicant: Sharmila Nair, Ph.D.
• Subject Area: Virology ; Immunology
• Term: from 2014 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 266373065

The type I interferon (IFN) response protects cells against invading viral pathogens. The cellular factors that mediate this defense are the products of interferon-stimulated genes (ISGs). Although hundreds of ISGs have been identified since their discovery, only a few have been characterized with respect to antiviral activity. For most ISG products, little is known about their antiviral potential, their target specificity and their mechanisms of action. Different ISGs are thought to have more potent antiviral activities toward different families of viruses. Additionally, some ISGs may be cell-type restricted and be more relevant for inhibiting a virus in specific tissues.Using gain of function/loss of function assays in neuronal cells, the Diamond lab identified the ISG- Immunity related GTPase (Irg) 1 as a potential antiviral factor against neurotropic viruses including West Nile virus (WNV) and other positive-strand RNA viruses. Irg1 belongs to the family of Ras-type GTPase where the GTP moiety serves as a biochemical switch. However, the mechanism by which Irg1 executes its antiviral effect currently remains unknown. Thus, the aim of this research proposal is to gain novel insights into Irg1 specific antiviral effector functions by:(1) Characterizing which stage of the West Nile replication cycle it restricts. The effect of the GTPase domain on Irg1 dependent antiviral responses will also be investigated. This information can be used subsequently to help define the specific antiviral mechanism of action of Irg1.(2) Determining its antiviral potential and target specificity against several neurotropic and other positive/ negative stranded RNA viruses. With the availability of the newly generated Irg1-/- mice developed by the Diamond group, the extent of its antiviral action against different virus groups will be tested. Moreover, the cell-type contribution of Irg1 to antiviral immunity also will be investigated. Clinically, IFN is used to treat several viral infections and is a principle component of Hepatitis B and Hepatitis C virus treatment. Given the clinical side effects of IFN treatment, and the natural ability of viruses to antagonize its signaling and activity, exploiting the actions of individual ISGs may be a preferable therapeutic strategy. Further insight into the biochemical mechanisms of these effectors may provide a platform for the development of alternatives to IFN-based therapies.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Michael Diamond, Ph.D.