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

Abstract

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

Nitric Oxide Modulates Macrophage Responses to Mycobacterium tuberculosis Infection through Activation of HIF-1α and Repression of NF-κB

“…We find that during M. tuberculosis infection NO is required for IFN-γ dependent stabilization of HIF-1α, a transcription factor we have recently shown to be critical for control of M. tuberculosis infection (16). Interestingly, we find that HIF-1α and iNOS are linked in a positive feedback loop during IFN-γ activation of M. tuberculosis infected macrophages.…”

The Tyrosine Kinase Inhibitor Gefitinib Restricts Mycobacterium tuberculosis Growth through Increased Lysosomal Biogenesis and Modulation of Cytokine Signaling

“…To assess growth, we used a luminescent reporter strain, TB-Lux, that expresses the bacterial luminescent operon lux CDABE that we have shown to be a linear reporter of bacterial number in macrophages. 23 Resting and IFN- γ -activated BMDM were infected with TB-lux and treated with gefitinib or gefitinib and IFN- γ for 4 days post-infection. As expected, gefitinib treatment inhibited replication of M. tuberculosis in macrophages, as did activation of the macrophages with IFN- γ (Figure 1A).…”

Interleukin-17 limits hypoxia-inducible factor 1α and development of hypoxic granulomas during tuberculosis

“…A recent study also showed that in a high-dose model of Mtb Erdman infection, mice deficient in HIF1α in myeloid cells demonstrated increased susceptibility to infection (40). HIF1α was shown to induce IFN-γ-mediated killing by activating aerobic glycolysis (40), suggesting that the pathways that modulate host protection versus pathology are finely balanced. However, the above studies were conducted in B6 mice; further studies on the role of HIF1α in human or nonhuman primate Mtb infection models may provide additional insights into the role of HIF1α in inducing pathology, as shown here in necrotic mouse models, versus protection as shown in the non-necrotic B6 mouse model of Mtb infection.…”

“…Interestingly, in a systemic Mycobacterium avium model of infection, mice deficient in HIF1α expression in myeloid cells demonstrated increased liver necrosis (39). A recent study also showed that in a high-dose model of Mtb Erdman infection, mice deficient in HIF1α in myeloid cells demonstrated increased susceptibility to infection (40). HIF1α was shown to induce IFN-γ-mediated killing by activating aerobic glycolysis (40), suggesting that the pathways that modulate host protection versus pathology are finely balanced.…”