Many viruses induce hepatitis in humans, highlighting the need to understand the underlying mechanisms of virus-induced liver pathology. Themurine coronavirus,mouse hepatitis virus(MHV), causes acute hepatitis in its natural host and provides a useful model for understanding virus interaction with liver cells. The MHV accessory protein,ns2, antagonizes thetype I interferonresponse and promotes hepatitis. We show that ns2 has 2′,5′-phosphodiesterase activity, which blocks the interferon inducible 2′,5′-oligoadenylate synthetase (OAS)-RNase L pathway to facilitate hepatitis development. Ns2 cleaves 2′,5′-oligoadenylate, the product of OAS, to prevent activation of the cellular endoribonuclease RNase L and consequently block viralRNA degradation. An ns2mutant viruswas unable to replicate in the liver or induce hepatitis in wild-type mice, but was highly pathogenic in RNase L deficient mice. Thus, RNase L is a critical cellular factor for protection against viral infection of the liver and the resulting hepatitis.
Our results underscore the important role of RNase L in host restriction of viral infection of the liver. The success of IFN-α treatment of chronichepatitis C virus(HCV) may depend in part on the susceptibility of viral RNA genome to degradation by RNase L, which cleaves single-stranded viral RNA on the 3′ sides of UU and UA dinucleotides. Cleavage of HCV genome RNA by RNase L releases a small RNA that is recognized byRIG-Iand thus serves to enhance IFN induction (Malathi et al., 2010). Indeed, the strains of HCV that are most susceptible to IFN-α treatment are those strains with genomes predicted to be most vulnerable to RNase L-mediated degradation (Han et al., 2004,Washenberger et al., 2007). Thus, enhancement of the activity of the OAS-RNase L pathway may have potential for antiviral therapy for liver infections. A possible approach to enhancing RNase L mediated viral RNA genome degradation might be to limit activities of enzymes that degrade 2-5A; treatment with an inhibitor for 2′-PDE was shown to decrease vaccinia virus replication in vitro (Kubota et al., 2004). In this regard, inhibitors of virus-encoded phosphodiesterases that degrade 2′,5′-oligoadenylates could provide an avenue for development of targeted antiviral drugs.
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