Rojas Jose Manuel, Centro de Investigación en Sanidad Animal (Animal Health Research Centre) CISA-INIA/CSIC

José M Rojas 1, Andrés Louloudes-Lázaro 1, Pablo Nogales-Altozano 1, Jeury Veloz 2,3, Ana B Carlón 1, Piet A Van Rijn 4,5, Verónica Martín 1, Ana Fernández-Sesma 2, Noemí Sevilla 1 1 Centro de Investigación en Sanidad Animal, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, Consejo Superior de Investigaciones Científicas (CISA-INIA-CSIC), Valdeolmos, Madrid, Spain 2 Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY USA 3 The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY USA 4 Department of Virology, Wageningen Bioveterinary Research, Lelystad, The Netherlands 5 Department of Biochemistry, Centre for Human Metabolomics, North-West University, Potchefstroom, South Africa

Pathogenesis and Immunity

Cyclic GMP-AMP synthase (cGAS) is a DNA sensing cellular receptor that induces IFN-I transcription in response to pathogen and host derived cytosolic DNA. It has also been shown to limit the replication of some RNA viruses. Some viruses have nonetheless evolved mechanisms to antagonize cGAS sensing. In this study, we evaluated the interaction between Bluetongue virus (BTV), the prototypical dsRNA virus of the Orbivirus genus and the Sedoreoviridae family, and cGAS. We found mitochondrial damage and DNA accumulation in the cytoplasm of cells infected with BTV, which could potentially result in type I IFN induction. BTV infection nonetheless blocks DNA-induced IFN-I transcription and prevents DNA sensing by inducing cGAS and STING degradation. Moreover, cGAS blockade increases BTV titers during infection confirming the relevance of this pattern recognition receptor in the antiviral response to BTV. We identify BTV-NS3 as the viral protein responsible for cGAS degradation, showing that NS3 physically interacts with cGAS and induces its degradation through an autophagy-dependent mechanism. Taken together, these findings identify for the first time a mechanism by which a dsRNA virus interferes with a DNA sensing pathway to evade the innate immune response.