Wall teichoic acid is required for DNA-triggered innate immune receptor activation by Staphylococcus aureus

Receptors that stimulate inflammation are commonly activated by ligands that are buried within microbial cells. The mechanisms that facilitate immunostimulatory ligand release from microbes during infection are largely undefined. Using the pathogen Staphylococcus aureus, we describe wall teichoic acid (WTA) as a critical mediator of DNA release from bacterial cells during infection. Mechanistically, we found that the α-glycosylated form of WTA, generated by the enzyme TarM, is the primary mediator of bacterial DNA release within macrophages. This process is antagonized by the enzyme O-acetyltransferase, which prevents WTA attachment to peptidoglycan. This competition among peptidoglycan modifying enzymes determines activation of cytosolic DNA receptors AIM2 and cGAS. WTA therefore operates as a meta-regulator of inflammation, by controlling the availability of microbial ligands that stimulate innate immunity.