Evasion of Antiviral Innate Immunity by Theiler's Virus L* Protein through Direct Inhibition of RNase L

Theiler's virus is a neurotropic picornavirus responsible for chronic infections of the central nervous system. the establishment of a persistent infection and the subsequent demyelinating disease triggered by the virus depend on the expression of l*,a viral accessory protein encoded by an alternative open reading frame of the virus. we discovered that l* potently inhibits the interferon-inducible oas/rnase l pathway. the antagonism of rnase l by l* was particularly prominent in macrophages where baseline oligoadenylate synthetase (oas) and rnase l expression levels are elevated,but was detectable in fibroblasts after ifn pretreatment. l* mutations significantly affected theiler's virus replication in primary macrophages derived from wild-type but not from rnase l-deficient mice. l* counteracted the oas/rnase l pathway through direct interaction with the ankyrin domain of rnase l,resulting in the inhibition of this enzyme. interestingly,rnase l inhibition was species-specific as theiler's virus l* protein blocked murine rnase l but not human rnase l or rnase l of other mammals or birds. direct rnase l inhibition by l* and species specificity were confirmed in an in vitro assay performed with purified proteins. these results demonstrate a novel viral mechanism to elude the antiviral oas/rnase l pathway. by targeting the effector enzyme of this antiviral pathway,l* potently inhibits rnase l,underscoring the importance of this enzyme in innate immunity against theiler's virus. © 2013 sorgeloos et al.