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.