TB remains a global epidemic infecting nearly 2.2 billion people worldwide and causing 1.4 million deaths annually. Understanding the mechanisms of how Mtb enters, maintains and emerges from a dormant state is a vitally important question in the TB field that has not been adequately addressed. New paradigms for how Mtb can persist for decades, and then suddenly reactivate to cause disease, are desperately needed to combat this global epidemic. Recently, hydrogen sulfide (H2S) has been identified as the third endogenously produced gasotransmitter in mammalian cells that is an important cell signalling molecule in numerous biological systems. One of the most exciting biological features of H2S is that it induces a state of “suspended animation”; a hibernation-like metabolic status characterized by a reversible marked reduction of energy expenditure. While H2S has overlapping functions with CO and NO, a role for H2S in Mtb disease progression remains unexplored. Our long-term goal is to dissect new molecular mechanisms that promote Mtb persistence within the host and to use this information to develop novel therapeutic approaches to treat or prevent TB. Our central hypothesis, based upon exciting preliminary data, is that Mtb infection triggers a localized increase of host-generated H2S that (i) induces a state of deeply reduced metabolism to impede an adequate immune response, and (ii) stimulates Mtb respiration and growth, to accelerate death of the host. The rationale of this proposal is that successful completion of our aims will establish a new paradigm for understanding Mtb disease and persistence. Once the mechanisms whereby Mtb persists are known, we anticipate that targeted pharmacological manipulation will result in novel and more effective approaches to the prevention and treatment of TB. We will apply novel techniques such as real-time extracellular metabolic flux analysis and stable isotope analysis of immune cells, transgenic H2S-deficient mice, and freshly resected human TB lung tissue from a well-established patient cohort in Durban, South Africa to accurately describe roles for H2S in the bioenergetics and immunometabolism of TB. The research is innovative, in our opinion, because it represents a substantive departure from the status quo by applying novel technologies and unique patient cohorts to examine the role of H2S in TB for the first time. This contribution is significant because it has the potential to make a lasting, positive change to existing paradigms in TB research, particularly into how the gasotransmitter H2S impacts Mtb energy metabolism and dormancy as well as dysregulation of innate and adaptive immune cells during infection.