Cyclic di-AMP in host–pathogen interactions

•C-di-AMP is synthesized by a wide range of pathogens.•C-di-AMP is necessary for bacterial growth.•C-di-AMP is sensed by the innate immune system.•The host cell restricts its response to bacterial c-di-AMP.•The pathogen shapes the host response to its advantage. Cyclic di-AMP (c-di-AMP) is a bacterial signaling nucleotide synthesized by several human pathogens. This widespread and specific bacterial product is recognized by infected host cells to trigger an innate immune response. Detection of c-di-AMP in the host cytosol leads primarily to the induction of type I interferon via the STING-cGAS signaling axis, while being also entangled in the activation of the NF-κB pathway. During their long-standing interaction, host and pathogens have co-evolved to control c-di-AMP activation of innate immunity. On the bacterial side, the quantity of c-di-AMP released inside cells allows to manipulate the host response to exacerbate infection by avoiding immune recognition or, at the opposite, by overloading the STING-cGAS pathway.