Bacteria infecting the cytosol can be detected through their metabolic products in the form of cyclic dinucleotides such as c-di-AMP. In Nature Medicine, Bishai and colleagues find that mycobacteria also produce c-di-AMP, which is released into the cytosol of infected macrophages. By using mycobacteria either deficient in or overexpressing the gene responsible for c-di-AMP production, the authors observe that type I interferon (IFN-I) secretion by infected macrophages is correlated with the amount of c-di-AMP. Overexpressing bacteria show reduced virulence and growth in vivo, whereas the knockouts have increased virulence. Detection of c-di-AMP is via a helicase (DDX41)-STING–mediated pathway but independent of the cytosolic pathogen sensor cGAS. Sensing of mycobacterial c-di-AMP results in the activation of autophagy. These data suggest that the sensing of c-di-AMP is also important for anti-mycobacterial responses and results in a potentially protective IFN-I and xenophagy response.

Nat. Med. (2 March 2015) doi:10.1038/nm.3813