A host type I interferon response is induced by cytosolic sensing of the bacterial second messenger cyclic-di-GMP

McWhirter, Sarah M.; Barbalat, Roman; Monroe, Kathryn M.; Fontana, Mary F.; Hyodo, Mamoru; Joncker, Nathalie T.; Ishii, Ken J.; Akira, Shizuo; Colonna, Marco; Chen, Zhijian J.; Fitzgerald, Katherine A.; Hayakawa, Yoshihiro; Vance, Russell E.

Our results suggest that cytosolic sensing of c-di-GMP is relatively specific. Other related small nucleic acid compounds such as GTP, cGMP, ppGpp, and pGpG did not trigger transcriptional induction of type I IFNs (Fig. 1) . In addition, c-di-GMP that was hydrolyzed by snake venom phosphodiesterase did not induce type I IFN (Fig. 1) . However, our results cannot eliminate the possibility that a metabolite of c-di-GMP, rather than c-di-GMP itself, is the true molecular moiety that is sensed in the cytosol. Elimination of this possibility awaits identification of the c-di-GMP sensor and biophysical or crystallographic characterization of its binding to c-di-GMP. Our results also cannot eliminate the possibility that c-di-GMP triggers type I IFN expression indirectly, for example, by stimulating the synthesis of a host ligand that functions as the "true" proximal trigger of type I IFN gene expression. It is also possible that c-di-GMP acts "pharmacologically" by disrupting host physiology in a way that results in type I IFN expression. Moreover, because the signaling triggered by c-di-GMP and cytosolic DNA are very similar, it is possible that the c-di-GMP pathway is a branch off of the DNA-sensing pathway rather than a fully independent pathway. However, even if these alternative models are correct, our data indicate that the pathway downstream of c-di-GMP contains at least some novel components and is at least partially independent of known cytosolic or TLR signaling pathways.