Ebola viruses (EBOVs) are NIAID category A priority pathogens that cause severe viral hemorrhagic fever. A critical research task is to define how the molecular interactions between filoviruses and the human host trigger life-threatening infections. Defining such interactions will shed light on the triggers of viral hemorrhagic fever and will facilitate prophylactic and therapeutic interventions for this frequently lethal syndrome. We hypothesize that evasion of host innate defenses, particularly interferon (IFN)-??? responses, is critical to the uncontrolled virus replication and inflammation characteristic of EBOV infections. We previously demonstrated that the EBOV VP35 protein inhibits production of IFN??? and, consistent with a critical role for VP35 as a virulence factor, a VP35 mutant EBOV defective for suppression of IFN??? responses was avirulent in guinea pigs. We also demonstrated that that the EBOV VP24 protein inhibits IFN-induced Jak-STAT signaling by preventing the trafficking of phosphorylated STAT1 to the nucleus. This project builds upon these and other observations regarding the function of VP35 and VP24 to define their mechanisms of action, their impact on EBOV replication and their impact on EBOV pathogenesis. Based on data demonstrating that interaction of VP24 with karyopherin alpha nuclear localization signal receptors inhibits phospho-STAT1 nuclear import, we will define the mechanism by which VP24 blocks STAT1 nuclear import and assess the impact of VP24 on the nucleo/cytoplasmic trafficking of other karyopherin alpha cargoes. We also observed that VP24 inhibits the induction of cellular antioxidant responses normally mediated by the transcription factor Nrf2. Because Nrf2- induced antioxidant responses have been increasingly implicated in responses, including innate immune responses, to virus infection;we will determine the mechanism by which EBOV VP24 inhibits the Nrf2-induced antioxidant responses and the consequences of this inhibition for innate immunity. As multiple mechanisms have been identified by which EBOV VP35 inhibits IFN??? signaling, including sequestration of dsRNAs, interference with the kinases IKK? and TBK-1 and inhibition of interferon regulatory factor 7 function;we will dissect out the contribution of these functions to inhibition of IFN??? production. Finally, mutant recombinant EBOVs will be generated to determine how VP24 and VP35 immune evasion functions contribute to viral replication and virulence. The results of these studies will shed light on the contribution of VP24 and VP35 to EBOV pathogenesis and identify viral functions that may be targeted for antiviral development.
Ebolaviruses (EBOVs) are emerging viruses that cause severe viral hemorrhagic fevers and are therefore considered a public health threat. Currently, the factors used by these viruses to cause severe illness are not well-defined. The experiments in this proposal will clarify the role of two viral proteins, VP24 and VP35, in EBOV disease and suggest new ways to prevent or treat these infections.
|Teixeira, Avelino; Yen, Benjamin; Gusella, Gabriele Luca et al. (2015) Prothymosin ? variants isolated from CD8+ T cells and cervicovaginal fluid suppress HIV-1 replication through type I interferon induction. J Infect Dis 211:1467-75|
|Shabman, Reed S; Jabado, Omar J; Mire, Chad E et al. (2014) Deep sequencing identifies noncanonical editing of Ebola and Marburg virus RNAs in infected cells. MBio 5:e02011|
|Basler, Christopher F (2014) New hope in the search for Ebola virus treatments. Immunity 41:515-7|
|Edwards, Megan R; Johnson, Britney; Mire, Chad E et al. (2014) The Marburg virus VP24 protein interacts with Keap1 to activate the cytoprotective antioxidant response pathway. Cell Rep 6:1017-25|
|Xu, Wei; Edwards, Megan R; Borek, Dominika M et al. (2014) Ebola virus VP24 targets a unique NLS binding site on karyopherin alpha 5 to selectively compete with nuclear import of phosphorylated STAT1. Cell Host Microbe 16:187-200|
|Basler, Christopher F; Woo, Patrick C Y (2014) Editorial overview: emerging viruses. Curr Opin Virol 5:v-vii|
|Yen, Benjamin; Mulder, Lubbertus C F; Martinez, Osvaldo et al. (2014) Molecular basis for ebolavirus VP35 suppression of human dendritic cell maturation. J Virol 88:12500-10|
|Basler, Christopher F (2014) Portrait of a killer: genome of the 2014 EBOV outbreak strain. Cell Host Microbe 16:419-21|
|Feagins, Alicia R; Basler, Christopher F (2014) The VP40 protein of Marburg virus exhibits impaired budding and increased sensitivity to human tetherin following mouse adaptation. J Virol 88:14440-50|
|Brown, Craig S; Lee, Michael S; Leung, Daisy W et al. (2014) In silico derived small molecules bind the filovirus VP35 protein and inhibit its polymerase cofactor activity. J Mol Biol 426:2045-58|
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