Antagonism of the antiviral OAS/RNase L pathway by Theiler's virus L* protein : molecular mechanisms and species-specificity

The DA strain of Theiler’s virus has a remarkable ability to evade the immune response of the host and to cause persistent infections of the central nervous system. During the chronic phase of infection, the virus is primarily detected in microglial cells, infiltrating macrophages and oligodendrocytes in the white matter of the spinal cord. The non-structural L* protein encoded by Theiler's virus was shown to enhance viral replication in macrophages in vitro and to be required for the establishment of persistent infections. Previous work in our lab revealed that L* directly interacts with RNase L and thereby inhibits the activity of this antiviral enzyme. Interestingly, RNase L antagonism by L* is a highly species-specific process; indeed, L* inhibits mouse RNase L but not its orthologues from other tested species. On the one hand, we characterized further the molecular mechanisms of RNase L antagonism by the Theiler’s virus L* protein. We identified a novel strategy of RNase L inhibition in which, upon binding to ankyrin repeats 1 and 2 of the mouse RNase L, L* competitively inhibits 2-5A binding to RNase L. Using chimeric MHV viruses expressing L*, we demonstrated that L* is able to counteract RNase L activity in vivo, in infected mice. On the other hand, we took advantage of the species-specificity of L* activity to identify the natural host of Vilyuisk human encephalitis virus (VHEV). VHEV was isolated from mice that were inoculated with CSF from a patient suffering from chronic encephalitis. It is therefore unclear whether the virus derives from the human sample or from the mice used to isolate the virus. We observed that L* of VHEV specifically binds to and inhibits mouse but not human RNase L, thereby showing that VHEV is of mouse origin and suggesting that it is a contaminant that originated from the mice that were used to inoculate the human sample.
(BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 2017