Elucidation of the Mechanism of Suppression of Type-I IFN Response by Equine Herpesvirus-1

The long-term goal of this project is to identify the key viral proteins that equine herpesvirus-1 (EHV-1) uses to repress the host cells’ type-I interferon (IFN) signaling during infection. EHV-1 is a worrying disease condition for many horse owners impacting significant economic losses to the equine industry. Earlier studies have demonstrated the importance of type-I IFN as the first line of defense against many viral infections. A recent finding from our group has revealed that EHV-1, irrespective of their genotype, has the ability to inhibit type-I interferon response in an equine endothelial cell culture (EEC) system. We identified that one of the mechanisms employed by EHV-1 to escape the host type-I interferon response involves blocking of an important transcription factor; interferon regulatory factor-3 (IRF-3). However, the effect of EHV-1 infection on other important players of the type-I IFN signaling pathway such as IRF-7, IRF-9, the signal transducer and activator of transcription-2 (STAT-2) still remains unknown. In order to come up with the development of potent antivirals or immunotherapeutic agents against EHV-1 infection, a detailed understanding of the various ways by which the virus suppresses the host type-I IFN antiviral activity is critical. The central hypothesis of this research is that EHV-1 can interfere with the key players of the host cells’ type-I interferon signaling thereby enabling viral spread and promoting disease manifestations. This project will aim at investigating the effect of EHV-1 on the cascade of outside-in type-I IFN signal transduction events during infection using our already established EEC model. Specifically, we will explore the effect of EHV-1 infection on molecular viral sensors such as the toll-like receptors (TLRs), and also investigate whether EHV-1 interferes with the activation of essential interferon transcription factors during infection.