How does Vaccinia virus inhibit the detection of cytosolic DNA by the innate immune system?

Vaccinia virus (VacV) is a large dsDNA virus belonging to the Poxviridae family. Due to its size, the VacV replication cycle occurs entirely within the cytoplasm of infected cells. This exposes the virus to the many intracellular DNA sensors found in human cells. Since its discovery in 2013, cyclic GMP-AMP Synthase (cGAS) has been shown to be the predominant cytoplasmic DNA sensor in many cell types, including keratinocytes. Once activated, cGAS generates the second messenger cGAMP to trigger IFNβ production, through the adaptor protein STING. VacV can limit IFN production by inhibiting this pathway at multiple points, but little is known about whether VacV is able to inhibit DNA sensing directly. To investigate this, intracellular DNA sensing within keratinocytes was analysed during VacV infection. Results showed that within 4 hours of infection VacV was able to induce the loss of cGAS to undetectable levels, effectively blocking the cell IFNβ response. Additional DNA sensors that cooperate with cGAS such as IFI16 remained unaffected, showing that cGAS is essential for the IFN response to VacV. Inhibition of host degradation pathways did not prevent cGAS loss during VacV infection, suggesting cGAS is directly targeted for enzymatic cleavage. This demonstrates a potential new mechanism VacV employs to limit DNA sensing through cGAS, although the viral proteins responsible remain elusive. Identification of these proteins may provide new treatments for certain autoimmune disease where overactivation of cGAS contributes to disease phenotype.