Abstract – Overview With about 10 million new cases of active disease and 1.8 million deaths annually, TB is a global health emergency. A distinguishing feature of TB disease is its biological heterogeneity, which manifests at the clinical level chiefly in 2 forms: disease progression and treatment response. The premise of this Program is that the heterogeneous outcomes of TB infection and treatment are determined by the interplay of competing regulatory networks between the pathogen and the host. Our primary goal is to apply systems biology approaches to elucidate the biological control underlying the variability of disease outcome and response to treatment. Our first specific aim is to define novel host regulators of TB disease progression in vivo, and the innate and adaptive networks they control. We will also seek to define novel Mtb regulators of TB treatment response, and the Mtb regulatory networks that they control. This work will allow us to produce and validate host and Mtb models of TB disease progression and treatment response. Altogether, this program addresses key unanswered questions that stymie efforts to combat the TB pandemic. Our team has perfected the required platforms and scientific approaches to execute this ambitious research plan in a timely and cost- effective manner. All the participating investigators have strong records of interacting productively, and of disseminating their data and reagents to the scientific community.