HIF-1α Is an Essential Mediator of IFN-γ-Dependent Immunity to Mycobacterium tuberculosis

The cytokine IFN-gamma coordinates macrophage activation and is essential for control of pathogens, including Mycobacterium tuberculosis. However, the mechanisms by which IFN-gamma controls M. tuberculosis infection are only partially understood. In this study, we show that the transcription factor hypoxia-inducible factor-1 alpha (HIF-1 alpha) is an essential mediator of IFN-gamma-dependent control of M. tuberculosis infection both in vitro and in vivo. M. tuberculosis infection of IFN-gamma-activated macrophages results in a synergistic increase in HIF-1 alpha protein levels. This increase in HIF-1 alpha levels is functionally important, as macrophages lacking HIF-1 alpha are defective for IFN-gamma-dependent control of infection. RNA-sequencing demonstrates that HIF-1 alpha regulates nearly one-half of all IFN-gamma-inducible genes during infection of macrophages. In particular, HIF-1 alpha regulates production of important immune effectors, including inflammatory cytokines and chemokines, eicosanoids, and NO. In addition, we find that during infection HIF-1 alpha coordinates a metabolic shift to aerobic glycolysis in IFN-gamma-activated macrophages. We find that this enhanced glycolytic flux is crucial for IFN-gamma-dependent control of infection in macrophages. Furthermore, we identify a positive feedback loop between HIF-1 alpha and aerobic glycolysis that amplifies macrophage activation. Finally, we demonstrate that HIF-1 alpha is crucial for control of infection in vivo as mice lacking HIF-1 alpha in the myeloid lineage are strikingly susceptible to infection and exhibit defective production of inflammatory cytokines and microbicidal effectors. In conclusion, we have identified HIF-1 alpha as a novel regulator of IFN-gamma-dependent immunity that coordinates an immunometabolic program essential for control of M. tuberculosis infection in vitro and in vivo.