To explore STING's impact on the DENV replication in mouse cells, we used WT (Sting +/+ ) and STING double knockout (Sting 2/2 ) mouse embryonic fibroblasts (MEFs). First, we infected WT and Sting 2/2 MEFs with two different DENV-2 strains, 16681 and NGC (a strain that was obtained after several passages in mouse brain) [37] , with an MOI of 5. Then, we measured the ability of the two DENV-2 strains to induce IFNb production, to replicate in these cells and to release infectious particles from those cells ( Figure 4A-4F ). Both DENV-2 strains induced significantly higher levels of IFNb in WT MEFs as compared to the Sting 2/2 MEFs ( Figure 4A and 4D) , underlining the relevance of STING in the signaling of type I IFN upon the infection with DENV. Consistent with the observed low induction of IFNb, Sting 2/2 MEFs were permissive to DENV replication while, despite the high MOI used, replication of DENV 16681 and NGC was rapidly controlled in WT MEFs ( Figure 4B and 4E) . The production of infectious particles by the two DENV-2 strains in WT and Sting 2/2 MEFs was measured by plaque assay and shows that the KO MEFs were more permissive to DENV infection than the WT MEFs and have very different peaks of infection ( Figure 2C and 2F). To test whether our observation was independent from the high MOI and viral strains used, we repeated the infection using different DENV serotypes (DENV-2 16681 strain, DENV-3 PR-6 strain and DENV-4 H-241 strain) and an MOI of 1, with similar results (data not shown). These results are likely due to the inability of DENV to inhibit the type I IFN signaling in mouse cells and the establishment of the antiviral state [31] Mutation of cleavage site for DENV-NS2B3 restores the ability of STING to induce type I IFN production upon DENV infection