Evasion of interferon responses by Ebola and Marburg viruses.
The filoviruses, Ebola virus (EBOV) and Marburg virus (MARV), cause frequently lethal viral hemorrhagic fever. These infections induce potent cytokine production, yet these host responses fail to prevent systemic virus replication. Consistent with this, filoviruses have been found to encode proteins VP35 and VP24 that block host interferon (IFN)-alpha/beta production and inhibit signaling downstream of the IFN-alpha/beta and the IFN-gamma receptors, respectively. VP35, which is a component of the viral nucleocapsid complex and plays an essential role in viral RNA synthesis, acts as a pseudosubstrate for the cellular kinases IKK-epsilon and TBK-1, which phosphorylate and activate interferon regulatory factor 3 (IRF-3) and interferon regulatory factor 7 (IRF-7). VP35 also promotes SUMOylation of IRF-7, repressing IFN gene transcription. In addition, VP35 is a dsRNA-binding protein, and mutations that disrupt dsRNA binding impair VP35 IFN-antagonist activity while leaving its RNA replication functions intact. The phenotypes of recombinant EBOV bearing mutant VP35s unable to inhibit IFN-alpha/beta demonstrate that VP35 IFN-antagonist activity is critical for full virulence of these lethal pathogens. The structure of the VP35 dsRNA-binding domain, which has recently become available, is expected to provide insight into how VP35 IFN-antagonist and dsRNA-binding functions are related. The EBOV VP24 protein inhibits IFN signaling through an interaction with select host cell karyopherin-alpha proteins, preventing the nuclear import of otherwise activated STAT1. It remains to be determined to what extent VP24 may also modulate the nuclear import of other host cell factors and to what extent this may influence the outcome of infection. Notably, the Marburg virus VP24 protein does not detectably block STAT1 nuclear import, and, unlike EBOV, MARV infection inhibits STAT1 and STAT2 phosphorylation. Thus, despite their similarities, there are fundamental differences by which these deadly viruses counteract the IFN system. It will be of interest to determine how these differences influence pathogenesis.
Basler
Christopher F
CF
Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029, USA. chris.basler@mssm.edu
Amarasinghe
Gaya K
GK
D021581:Active Transport, Cell Nucleus; D000818:Animals; D029043:Ebolavirus / Q000472:pathogenicity / Q000502:physiology*; D019142:Hemorrhagic Fever, Ebola / Q000276:immunology* / Q000635:transmission / Q000821:virology*; D006801:Humans; D050835:Interferon Regulatory Factors / Q000378:metabolism; D007372:Interferons / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008379:Marburg Virus Disease / Q000276:immunology / Q000635:transmission / Q000821:virology; D029024:Marburgvirus / Q000472:pathogenicity / Q000502:physiology*; D015398:Signal Transduction; D014764:Viral Proteins / Q000276:immunology / Q000378:metabolism; D054334:Viral Regulatory and Accessory Proteins / Q000276:immunology / Q000378:metabolism; D014779:Virus Replication; D028901:alpha Karyopherins / Q000378:metabolism
D050835:Interferon Regulatory Factors; C446938:VP24 protein, Ebola virus; C080980:VP35 protein, filovirus; D014764:Viral Proteins; D054334:Viral Regulatory and Accessory Proteins; D028901:alpha Karyopherins; D007372:Interferons
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