Ebola virus is a highly dangerous pathogen causing hemorrhagic fever in humans. Currently, there is no vaccine or effective treatment available for Ebola virus infection. While multiple factors contribute to the pathogenesis of Ebola virus infection, the ability of Ebola virus VP35 to abate the host interferon response is critical in determining the outcome of viral infection. VP35 is an essential component required for the Ebola virus RNA replication and nucleocapsid assembly. In addition, VP35 is implicated as an interferon antagonist. When expressed in mammalian cells, VP35 blocked interferon-beta expression and induction of interferon-stimulated response genes triggered by RNA or virus infection. These observations are consistent with previous findings that in cells infected with Ebola virus, production of interferon or expression of interferon-inducible genes is suppressed, for example, MHC class I, double-stranded RNA-dependent protein kinase, and interferon regulatory factor-1. Recent studies showed that mice lacking an interferon alpha/beta response resemble primates in their susceptibility to rapidly progressive, overwhelming Ebola virus infection. These studies suggest that VP35 is a viral factor that interferes with one or more components of the interferon pathways, therefore inhibiting host interferon response that results in rapid spread and dissemination of viruses. In this proposal, the biological functions of VP35 in interferon response will be investigated using mammalian cell lines and a surrogate infection system. Deletions or site-specific mutations will be used to define the functional modules of VP35. Furthermore, biochemical and genetic approaches will be employed to examine the nature of interactions between VP35 and the interferon pathways. Because of the potential of VP35 as a vaccine and antiviral target, the proposed studies should not only provide insight into the pathogenesis of Ebola virus infection but could also lead to the development of antiviral therapeutics.
| Feng, Zongdi; Cerveny, Melissa; Yan, Zhipeng et al. (2007) The VP35 protein of Ebola virus inhibits the antiviral effect mediated by double-stranded RNA-dependent protein kinase PKR. J Virol 81:182-92 |
