Resistance to ectromelia virus infection requires cGAS in bone marrow-derived cells which can be bypassed with cGAMP therapy

Author summary During primary acute systemic viral infections, cells sensing virus through Pathogen Recognition Receptors (PRR) can produce Type I interferons (IFN-I) to induce an anti-viral state that curbs viral spread and protect from viral disease. The dissection of the specific cells, receptors and downstream pathways required for IFN-I production during viral infection in vivo is necessary to improve anti-viral therapies. In this study, we demonstrated that the cytosolic PRR cGAS in hematopoietic cells but not in parenchymal cells is required for protection against ectromelia virus, the archetype for viruses that spread through the lympho-hematogenous route. We also show that cGAS deficiency can be bypassed by local administration of cyclic-GMP-AMP (cGAMP) by inducing IFN-I only in the skin and in the presence of virus. Our study provides novel insights into the cGAS signaling pathway and highlights the potential of cGAMP as an efficient anti-viral treatment. Cells sensing infection produce Type I interferons (IFN-I) to stimulate Interferon Stimulated Genes (ISGs) that confer resistance to viruses. During lympho-hematogenous spread of the mouse pathogen ectromelia virus (ECTV), the adaptor STING and the transcription factor IRF7 are required for IFN-I and ISG induction and resistance to ECTV. However, it is unknown which cells sense ECTV and which pathogen recognition receptor (PRR) upstream of STING is required for IFN-I and ISG induction. We found that cyclic-GMP-AMP (cGAMP) synthase (cGAS), a DNA-sensing PRR, is required in bone marrow-derived (BMD) but not in other cells for IFN-I and ISG induction and for resistance to lethal mousepox. Also, local administration of cGAMP, the product of cGAS that activates STING, rescues cGAS but not IRF7 or IFN-I receptor deficient mice from mousepox. Thus, sensing of infection by BMD cells via cGAS and IRF7 is critical for resistance to a lethal viral disease in a natural host.