Type I IFN production is an important host immune response against viral and
bacterial infections. However, little is known about the
ligands and corresponding host receptors that trigger type I IFN production during
bacterial infections. We used a model intracellular pathogen, Francisella novicida, to begin characterizing the type I IFN response to bacterial pathogens. F. novicida replicates in the cytosol of host cells and elicits a robust type I IFN response that is largely TLR independent, but is dependent on the adapter molecule
STING, suggesting that the type I IFN stimulus during F. novicida
infection is cytosolic. In this study, we report that the cytosolic
DNA sensors,
cyclic GMP-AMP synthase (cGAS) and Ifi204, are both required for the
STING-dependent type I IFN response to F. novicida
infection in both primary and immortalized murine macrophages. We created cGAS, Ifi204, and
Sting functional knockouts in RAW264.7 macrophages and demonstrated that cGAS and Ifi204 cooperate to sense dsDNA and activate the
STING-dependent type I IFN pathway. In addition, we show that dsDNA from F. novicida is an important type I IFN stimulating
ligand. One outcome of cGAS-
STING signaling is the activation of the absent in
melanoma 2
inflammasome in response to F. novicida
infection. Whereas the absent in
melanoma 2
inflammasome is beneficial to the host during F. novicida
infection, type I IFN signaling by
STING and
IFN regulatory factor 3 is detrimental to the host during F. novicida
infection. Collectively, our studies indicate that cGAS and Ifi204 cooperate to sense cytosolic dsDNA and F. novicida
infection to produce a strong type I IFN response.