title: Evasion of antiviral innate immunity by Theiler's virus L* protein through direct inhibition of RNase L.
abstract: 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.
authors.affiliation: Université Catholique de Louvain, de Duve Institute, Brussels, Belgium.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Sorgeloos
authors.forename: Babal Kant
authors.initials: BK
authors.lastname: Jha
authors.forename: Robert H
authors.initials: RH
authors.lastname: Silverman
authors.forename: Thomas
authors.initials: T
authors.lastname: Michiels
mesh_terms: D000818:Animals; D018188:Cardiovirus Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D006224:Cricetinae; D004722:Endoribonucleases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D057131:Immune Evasion / Q000502:physiology*; D007113:Immunity, Innate; D051379:Mice; D008817:Mice, Mutant Strains; D017434:Protein Structure, Tertiary; D013045:Species Specificity; D017945:Theilovirus / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D014764:Viral Proteins; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease