Suppression of the Equine Type-1 Interferon Response by Equine Herpesvirus-1

Equine herpesvirus-1 (EHV-1) is one of the most important viral diseases of horses worldwide, a cause of respiratory disease, abortion and potentially deadly neurologic disease. Available vaccines have been incapable of fully controlling this disease. Part of the reason is that, like other herpesviruses, EHV-1 has ways of obstructing the horse’s immune responses. Our just-concluded AQHA-supported project, “Equine herpesvirus-1 and the Type-I interferon response,” has found evidence that one of these obstructions mounted by EHV-1 is suppression of the horse’s Type-I interferon (hereafter IFNá/â) response. The IFNá/â response is one of the front lines of defense against viral infections, and stimulates both early non-specific (innate) protective responses and also later specific (adaptive) responses against the infecting virus. Following upon our previous study, we now propose to elucidate the molecular mechanism by which EHV-1 accomplishes this suppression. The IFNá/â response has 3 components: sensitization, induction, and amplification. We plan to test each of these for evidence of viral suppression of its key molecular pathways. We will search for virus-induced disruption in expression or activity of cellular TLR pattern recognition receptors and IRF3/7 or NF-êB signaling pathways that initially sensitize the IFNâ mechanism; the JAK-STAT signaling pathways by which IFNâ induces IFNá production; and representative IFN-stimulated genes that amplify the IFNá/â response into a state of antiviral resistance. Finally, while identification of the specific viral protein(s) responsible for suppression of the IFNá/â response is not achievable in this project timeframe, we propose here to develop the key molecular tools which will facilitate that work in future: i.e. plasmids bearing key equine genomic promoter sequences for the IFNá/â response, and a marker gene (luciferase) responsive to effects upon those promoters. This proposal is the next step in our AQHA-supported line of research whose ultimate goal is successful control of EHV-1.