Abstract
Tuberculosis is the single biggest infectious killer in the world and presents a major global health challenge. Antimicrobial therapy requires many months of multiple drugs and incidences of drug resistant tuberculosis continues to rise. Consequently, research is now focused on the development of therapies to support the function of infected immune cells. HIF1α-mediated induction of aerobic glycolysis is integral to the host macrophage response during infection with Mtb, as this promotes bacillary clearance. Some iron chelators have been shown to modulate cellular metabolism through the regulation of HIF1α. We examined if the iron chelator, desferrioxamine (DFX), could support the function of primary human macrophages infected with Mtb. Using RT-PCR, we found that DFX promoted the expression of key glycolytic enzymes in Mtb-infected primary human MDMs and human alveolar macrophages. Using Seahorse technology, we demonstrate that DFX enhances glycolytic metabolism in Mtb-stimulated human MDMs, while helping to enhance glycolysis during mitochondrial distress. Furthermore, the effect of DFX on glycolysis was not limited to Mtb infection as DFX also boosted glycolytic metabolism in uninfected and LPS-stimulated cells. DFX also supports innate immune function by inducing IL1β production in human macrophages during early infection with Mtb and upon stimulation with LPS. Moreover, using hypoxia, Western blot and ChIP-qPCR analyses, we show that DFX modulates IL1β levels in these cells in a HIF1α-mediated manner. Collectively, our data suggests that DFX exhibits potential to enhance immunometabolic responses and augment host immune function during early Mtb infection, in selected clinical settings.
Highlights
Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is the leading cause of death by a single infectious agent worldwide, killing approximately 1.7 million individuals in 2018 [1, 2]
To explore if DFX demonstrates potential as a Host-directed therapy (HDT) during early bacterial infection, we examined if DFX could enhance macrophage metabolism and function in a human macrophage model of Mtb infection
We show that the iron chelator DFX enhances glycolytic metabolism and boosts immune responses in a human macrophage model of early Mtb infection, and in cells stimulated with LPS (Figure 7)
Summary
Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is the leading cause of death by a single infectious agent worldwide, killing approximately 1.7 million individuals in 2018 [1, 2]. Desferrioxamine Enhances Human Macrophage Metabolism to combat infectious diseases, which aims to support the function of infected host cells [3]. As immunometabolic reprogramming is integral to host defense during bacterial infection, supporting these bioenergetic pathways through the use of HDTs may offer alternative therapeutic approaches [1]. Infection of human macrophages with Mtb is associated with increased extracellular lactate levels [10]. This shift to aerobic glycolysis during Mtb infection is coupled to the ability of human macrophages to produce specific pro-inflammatory cytokines, such as mature IL1β, to lower the burden of infection [10]. In vivo studies highlight the crucial roles of IL1β and TNFα during the early stages of tuberculosis infection [12, 13]
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