Intracellular bacteria engage a STING-TBK1-MVB12b pathway to enable paracrine cGAS-STING signaling

The innate immune system is crucial for eventual control of infections, but may also contribute to pathology. Listeria monocytogenes is an intracellular gram-positive bacteria and a major cause of food-borne disease. However, important knowledge on the interactions between L. monocytogenes and the immune system is still missing. Here we report that Listeria DNA is sorted into extracellular vesicles (EV)s in infected cells and delivered to bystander cells to stimulate the cGAS-STING pathway. This was also observed during infections with Francisella tularensis and Legionella pneumophila. We identify the multivesicular body protein MVB12b as a target for TBK1 phosphorylation, which is essential for sorting of DNA into EVs and stimulation of bystander cells. EVs from Listeria-infected cells inhibited T cell proliferation, and primed T cells for apoptosis. Collectively, we describe a pathway for EV-mediated delivery of foreign DNA to bystander cells, and suggest that intracellular bacteria exploit this pathway to impair anti-bacterial defense.