Dual Role of Hypoxia-Inducible Factor 1 α in Experimental Pulmonary Tuberculosis: Its Implication as a New Therapeutic Target

Baay-Guzmán, Guillermina; Durán-Padilla, Marco A; Rangel-Santiago, Jesus; Tirado-Rodríguez, Belén; Antonio‐Andres, Gabriela; Barrios-Payán, Jorge; Mata-Espinosa, Dulce; Klünder‐Klünder, Miguel; Vega, Mario I.; Hernández-Pando, Rogelio; Huerta-Yépez, Sara

doi:10.2217/fmb-2017-0168

Cited by 36 publications

(29 citation statements)

References 39 publications

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“…This is followed by a later adaptation/resolution phase (24–48 h post-infection) in which there is a down regulation of immune response genes and a transition from glycolysis to mitochondrial oxidation in mouse BMDMs. Another study using a mouse model of progressive pulmonary tuberculosis, also demonstrated that the Mtb H37Rv infection is divided into two phases (Baay-Guzman et al, 2018 ). During the first phase, corresponding to the first month, granulomas are produced.…”

Section: Macrophage Response To Mtb Infectionmentioning

confidence: 99%

“…When a potential HDT, 2-methoxyestradiol that inhibits HIF-1α, was administered during the first phase, the lung bacillary loads were greater than the control group, and a greater area of the lung surface was affected by pneumonia. But when 2-methoxyestradiol was administered in the second phase, both the lung bacillary load and lung surface area affected by pneumonia were significantly reduced (Baay-Guzman et al, 2018 ). However, it is not known if this biphasic response is exhibited in infected human macrophages.…”

Section: Macrophage Response To Mtb Infectionmentioning

confidence: 99%

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Relevance of the Warburg Effect in Tuberculosis for Host-Directed Therapy

Cumming

Pacl

Steyn

2020

Front. Cell. Infect. Microbiol.

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Tuberculosis (TB) was responsible for more deaths in 2019 than any other infectious agent. This epidemic is exacerbated by the ongoing development of multi-drug resistance and HIV co-infection. Recent studies have therefore focused on identifying host-directed therapies (HDTs) that can be used in combination with anti-mycobacterial drugs to shorten the duration of TB treatment and improve TB outcomes. In searching for effective HDTs for TB, studies have looked toward immunometabolism, the study of the role of metabolism in host immunity and, in particular, the Warburg effect. Across a variety of experimental paradigms ranging from in vitro systems to the clinic, studies on the role of the Warburg effect in TB have produced seemingly conflicting results and contradictory conclusions. To reconcile this literature, we take a historical approach to revisit the definition of the Warburg effect, reexamine the foundational papers on the Warburg effect in the cancer field and explore its application to immunometabolism. With a firm context established, we assess the literature investigating metabolism and immunometabolism in TB for sufficient evidence to support the role of the Warburg effect in TB immunity. The effects of the differences between animal models, species of origin of the macrophages, duration of infection and Mycobacterium tuberculosis strains used for these studies are highlighted. In addition, the shortcomings of using 2-deoxyglucose as an inhibitor of glycolysis are discussed. We conclude by proposing experimental criteria that are essential for future studies on the Warburg effect in TB to assist with the research for HDTs to combat TB.

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Section: Macrophage Response To Mtb Infectionmentioning

confidence: 99%

Section: Macrophage Response To Mtb Infectionmentioning

confidence: 99%

Relevance of the Warburg Effect in Tuberculosis for Host-Directed Therapy

Cumming

Pacl

Steyn

2020

Front. Cell. Infect. Microbiol.

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“…Although not stressed by the authors, it is notable that these AM displayed a foamy phenotype unlike AM from WT mice (52), arguing that the uncontrolled activation of HIF-1α may contribute to FM formation. In line with this, it has recently been described that the activation of HIF-1α during late stages of infection with Mtb promotes the survival of infected FM (53), and that the activation of HIF-1α mediated by IFN-γ contributes to the formation of LBs in macrophages infected with Mtb (54). At least two hypotheses can explain how HIF-1α activation contributes to FM formation: 1) by suppressing FAO, and/or 2) by inducing endogenous fatty acid synthesis.…”

Section: Discussionmentioning

confidence: 65%

Mycobacterium tuberculosisModulates the Metabolism of Alternatively Activated Macrophages to Promote Foam Cell Formation and Intracellular Survival

Genoula

Franco

Maio

et al. 2019

Preprint

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1The ability of Mycobacterium tuberculosis (Mtb) to persist inside host cells relies on 2 metabolic adaptation, like the accumulation of lipid bodies (LBs) in the so-called 3 foamy macrophages (FM). Indeed, FM are favorable to Mtb. The activation state of 4 macrophages is tightly associated to different metabolic pathways, such as lipid 5 metabolism, but whether differentiation towards FM differs between the 6 macrophage activation profiles remains unclear. Here, we aimed to elucidate if 7 distinct macrophage activation states exposed to a tuberculosis-associated 8 microenvironment can accumulate LBs, and its impact on the control of infection. 9We showed that signal transducer and activator of transcription 6 (STAT6) 10 activation in interleukin (IL)-4-activated human macrophages (M(IL-4)) prevents FM 11 formation induced by pleural effusion from patients with tuberculosis. In these cells, 12 LBs are disrupted by lipolysis, and the released fatty acids enter the -oxidation 13 (FAO) pathway fueling the generation of ATP in mitochondria. We demonstrated 14 that inhibition of the lipolytic activity or of the FAO drives M(IL-4) macrophages into 15 FM. Also, exhibiting a predominant FAO metabolism, mouse alveolar macrophages 16 are less prone to become FM compared to bone marrow derived-macrophages. 17 Upon Mtb infection, M(IL-4) macrophages are metabolically re-programmed 18 towards the aerobic glycolytic pathway and evolve towards a foamy phenotype, 19which could be prevented by FAO activation or inhibition of the hypoxia-inducible 20 factor 1-alpha (HIF-1α)-induced glycolytic pathway. In conclusion, our results 21 demonstrate a role for STAT6-driven FAO in preventing FM differentiation, and 22

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“…However, therapeutic stabilization of HIF1α has to be tailored individually. For instance, in a model of progressive pulmonary tuberculosis in BALB/c mice, the blockage of HIF1α worsened the disease during the early phase of infection, while it decreased bacterial load during late tuberculosis [212].…”

Section: Hif Stabilization As Therapeutic Strategy For the Control Ofmentioning

confidence: 99%

Mechanisms controlling bacterial infection in myeloid cells under hypoxic conditions

Hayek

Schatz

Bogdan

et al. 2020

Cell. Mol. Life Sci.

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Various factors of the tissue microenvironment such as the oxygen concentration influence the host–pathogen interaction. During the past decade, hypoxia-driven signaling via hypoxia-inducible factors (HIF) has emerged as an important factor that affects both the pathogen and the host. In this chapter, we will review the current knowledge of this complex interplay, with a particular emphasis given to the impact of hypoxia and HIF on the inflammatory and antimicrobial activity of myeloid cells, the bacterial responses to hypoxia and the containment of bacterial infections under oxygen-limited conditions. We will also summarize how low oxygen concentrations influence the metabolism of neutrophils, macrophages and dendritic cells. Finally, we will discuss the consequences of hypoxia and HIFα activation for the invading pathogen, with a focus on Pseudomonas aeruginosa, Mycobacterium tuberculosis, Coxiella burnetii, Salmonella enterica and Staphylococcus aureus. This includes a description of the mechanisms and microbial factors, which the pathogens use to sense and react to hypoxic conditions.

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Dual Role of Hypoxia-Inducible Factor 1 α in Experimental Pulmonary Tuberculosis: Its Implication as a New Therapeutic Target

Abstract: HIF-1α has a dual role in experimental TB. This finding could have therapeutic implications because combined treatment with 2-methoxyestradiol and antibiotics appeared to eliminate mycobacteria more efficiently than conventional chemotherapy during advanced disease.

Cited by 36 publications

References 39 publications

Relevance of the Warburg Effect in Tuberculosis for Host-Directed Therapy

Relevance of the Warburg Effect in Tuberculosis for Host-Directed Therapy

Mycobacterium tuberculosisModulates the Metabolism of Alternatively Activated Macrophages to Promote Foam Cell Formation and Intracellular Survival

Mechanisms controlling bacterial infection in myeloid cells under hypoxic conditions

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