Mycobacterium tuberculosis is one of the world's most successful human pathogens, infecting over 1.7 billion people worldwide. A key to its success is the ability to survive and replicate within macrophages through the use of a type VII secretion system, ESX-1. Upon phagocytosis, M. tuberculosis establishes a specialized phagosomal environment within macrophages, allowing for intracellular replication, persistence, and communication with the host cytoslic environment. Mycobacterial mutants defective in genes necessary for ESX-1 secretion are attenuated within infected macrophages and animal models of infection. While much work has been done to detail the molecular mechanism of ESX-1 secretion, little is still known about how the ESX-1 system modulates and affects the host-response during M. tuberculosis infection.

Through the use of gene expression arrays and microscopy analysis we demonstrate that the ESX-1 system of M. tuberculosis activates two key innate immune responses during infection of macrophages. One response is the transcription of type I interferons and induction of interferon stimulated genes (ISGs). The second response is ubiquitin mediated selective autophagy of the mycobacterial phagosome. Surprisingly, we demonstrate that both pathways are activated through a common mechanism via ESX-1 dependent release of mycobacterial DNA within the host cytosol. Activation of host DNA sensing machinery by mycobacterial DNA stimulates the STING-TBK1 pathway which simultaneous activates both the transcriptional induction of ISGs and recruitment of autophagic adaptors.