Summary
Toll Like Receptor 9 (TLR9), its adapter MyD88, the downstream transcription factor interferon regulatory factor 7 (IRF7) and type I interferons (IFN-I) are all required for resistance to infection with ectromelia virus (ECTV). However, it is not known how or in which cells these effectors function to promote survival. Here, we showed that after infection with ECTV, the TLR9-MyD88-IRF7 pathway was necessary in CD11c+ cells for the expression of proinflammatory cytokines and the recruitment of inflammatory monocytes (iMo) to the draining lymph node (D-LN). In the D-LN, the major producers of IFN-I were infected iMo, which used the DNA sensor-adapter STING to activate IRF7 and nuclear factor κB (NF-κB) signaling to induce the expression of IFNα and IFNβ, respectively. Thus, in vivo, two pathways of DNA pathogen sensing act sequentially in two distinct cell types to orchestrate resistance to a viral disease.