Although type I IFNs are primarily considered to be antiviral cytokines (Stetson and Medzhitov, 2006b) , there is growing appreciation for their complex role in bacterial infections as well. Indeed, it is clear that type I IFNs are induced by many, if not all, bacterial pathogens, and can contribute to diverse outcomes in vivo (Coers et al., 2000; O'Riordan et al., 2002; Opitz et al., 2006; Stetson and Medzhitov, 2006a; Henry et al., 2007; Roux et al., 2007; Stanley et al., 2007; Charrel-Dennis et al., 2008) . For several bacterial pathogens, (a) the c-di-GMP compound was chemically synthesized and >98% pure by HPLC (not depicted), (b) phosphodiesterase treatment of c-di-GMP resulted in a product that is no longer stimulatory ( Fig. 1 E) , and (c) macrophages deficient in all TLR signaling and unable to respond to LPS still responded to c-di-GMP (see below). Thus, these observations suggest that c-di-GMP is sensed in the cytosol, resulting in a potent induction of type I IFN in bone marrow macrophages.