Ebola viruses are highly pathogenic agents of viral hemorrhagic fever and are considered potential agents of bioterrorism. I previously demonstrated that the Ebola virus VP35 protein functions as an IFN antagonist. Subsequent experiments indicate that VP35 specifically inhibits expression of type I IFN genes, and that this is accomplished, at least in part, by blocking the activation of the transcription factor IRF-3. Ebola virus infection has also been reported to prevent cells from responding to IFN. Therefore, I screened Ebola virus proteins for their ability to prevent IFN beta-mediated activation of an IFN-responsive reporter gene. In doing so, I identified the Ebola virus VP24 protein as a putative inhibitor of IFN signaling. Based on analogy with other viruses, I hypothesize that the anti-IFN functions of VP35 and VP24 will play an important rote in Ebola virus pathogenesis. This application seeks to fully define the mechanisms by which the individual VP35 and VP24 proteins counteract the host IFN response using transfection-based assays and to assess the importance of these functions in the context of Ebola virus infected cells using genetically engineered, recombinant Ebola viruses.
The specific aims of this application are to: ? 1. Define the molecular mechanism by which the Ebola virus VP35 protein blocks the induction of IFN beta gene expression. ? 2. Define the mechanism by which the Ebola virus VP24 protein blocks transcriptional activation mediated by IFN. ? 3. Assess the significance of the VP35 and VP24 anti-IFN functions in the context of Ebola virus infection using genetically engineered mutant viruses. ? ? The experiments in this application should define the mechanisms by which the Ebola virus VP35 and VP24 proteins inhibit the IFN-response and assess whether these proteins exert anti-IFN functions in infected cells. If this much proves successful, we will be in a position to (1) identify the specific cellular factors, which interact with these viral proteins, and (2) to assess the role of VP35 and VP24 in Ebola virus pathogenesis in animal models. VP35 and VP24 may also prove to be attractive targets for new antiviral agents. Inhibition of anti-IFN factors may sensitize Ebola virus infected cells to the antiviral effects of IFN and may also enhance the effect of antiviral agents. ? ?
| Cardenas, Washington B; Loo, Yueh-Ming; Gale Jr, Michael et al. (2006) Ebola virus VP35 protein binds double-stranded RNA and inhibits alpha/beta interferon production induced by RIG-I signaling. J Virol 80:5168-78 |
| Dolnik, Olga; Volchkova, Valentina; Garten, Wolfgang et al. (2004) Ectodomain shedding of the glycoprotein GP of Ebola virus. EMBO J 23:2175-84 |
| Kash, John C; Basler, Christopher F; Garcia-Sastre, Adolfo et al. (2004) Global host immune response: pathogenesis and transcriptional profiling of type A influenza viruses expressing the hemagglutinin and neuraminidase genes from the 1918 pandemic virus. J Virol 78:9499-511 |
