Interferon Antagonism as a Common Virulence Factor of Hemorrhagic Fever Viruses

摘要

We examined the ability of viruses in the Hantavirus and Nairovirus genera of the family Bunyaviridae to interfere with host signaling pathways involved in innate immunity. For the nairovirus, Crimean Congo hemorrhagic fever virus (CCHFV), we found that the viral polymerase gene contains a predicted ovarian tumor (OTU) protease domain that functions to deconjugate ubiquitin and interferon stimulated gene product 15 (ISG15) from host proteins. Both ubiquitin and ISG15 reversibly conjugate to proteins via a conserved LRLRGG C-terminal motif, mediating important innate antiviral responses. We showed that the OTU domain-containing protease of CCHFV hydrolyzes ubiquitin and ISG15 from many cellular target proteins. This broad activity contrasts with the target specificity of known mammalian OTU domaincontaining proteins. The biological significance of this activity of viral OTU domain-containing proteases was evidenced by their capacity to inhibit nuclear factor kappa B (NF- kB) dependent signaling and to antagonize the antiviral effects of ISG15. The deconjugating activity of viral OTU proteases represents a novel viral immune evasion mechanism that inhibits ubiquitin- and ISG15-dependent antiviral pathways. For the hantavirus, Hantaan virus (HTNV), we found that the nucleocapsid protein was able to inhibit tumor necrosis factor alpha (TNF- alpha)-induced activation of NF-kB as measured by a reporter assay and activation of endogenous p65, a NF-kB subunit. We showed an interaction between HTNV N protein and importin-alpha, a nuclear import molecule responsible for shuttling NF-kB to the nucleus. These data suggest that HTNV N protein can sequester NF-kB in the cytoplasm, thus inhibiting its activity.