AMPK-Targeted Effector Networks in Mycobacterial Infection

Abstract

AMP-activated protein kinase (AMPK), a key metabolic regulator, plays an essential role in the maintenance of energy balance in response to stress. Tuberculosis (TB), primarily caused by the pathogen Mycobacterium tuberculosis (Mtb), remains one of the most important infectious diseases worldwide, characterized by both high incidence and mortality. Development of new preventive and therapeutic strategies against TB requires a profound understanding of the various host-pathogen interactions that occur during infection. Emerging data suggest that AMPK plays an essential regulatory role in host autophagy, mitochondrial biogenesis, metabolic reprogramming, fatty acid β-oxidation, and the control of pathologic inflammation in macrophages during Mtb infection. As described in this review, recent studies have begun to define the functional properties of AMPK modulators capable of restricting intracellular bacteria and promoting host defenses. Several host defense factors in the context of AMPK activation also participate in autophagic and non-autophagic pathways in a coordinated manner to enhance antimicrobial responses against Mtb infection. A better understanding of these AMPK-targeted effector networks offers significant potential for the development of novel therapeutics for human TB and other infectious diseases.

Keywords: AMPK; autophagy; immunometabolism; macrophage; mitochondria; mycobacteria.

FIGURE 1

A brief summary of reciprocal regulation between AMPK and mTOR pathways. AMPK is activated by upstream signaling pathways, including LKB1, CaMKKII, and TAK1. AMPK pathway inhibits mTOR signaling, through at least two mechanisms, i.e., phosphorylation of TSC2 via Rheb, and direct phosphorylation of RAPTOR. In addition, mTOR-S6K1 signaling pathway inhibits AMPK activation through inactivation of TAK1.

FIGURE 2

AMPK-mTOR signaling pathways during Mtb infection. During infection, Mtb can activate mTOR pathway to enhance lipid body formation and ULK1 inhibition. AMPK activation, which is induced by AMP/ATP ratio, LKB1, intracellular calcium influx, as well as IRGM, is required for autophagy activation through ULK1 phosphorylation at Ser317/555/777. Either adaptive (Th1 cytokine IFN-γ) or innate (NOD2) signaling can induce IRGM activation, which is required for autophagy activation. AMPK-mediated Beclin-1 phosphorylation also activates autophagy to enhance phagosomal maturation. AMPK and mTOR pathways reciprocally inhibit each other to regulate autophagy, metabolism, and inflammatory responses in host cells during Mtb infection. AMPK-mediated TFEB activation leads to lysosomal activation and fatty acid β-oxidation to suppress lipid body formation. Mtb-mediated Akt phosphorylation can inhibit Foxo3A activation, which is also required for autophagy activation in the host cells.

FIGURE 3

Summary of the immunometabolism in macrophages and DCs. In M1 and DCs, LPS stimulation leads to the upregulation of aerobic glycolysis, and altered TCA cycle with aberrant increase of several metabolic intermediates including succinate, citrate, and itaconate, which act as signaling and effector molecules in inflammatory responses and infection. In DCs, metabolic reprogramming results in the increased fatty acid synthesis through recharging NADPH and utilization of citrate. In M2 macrophages, the Krebs cycle and OXPHOS are intact to drive immunosuppression and the resolution of inflammation.

FIGURE 4

Regulation of immunometabolism in macrophages infected with Mtb. In early phase of Mtb infection, mTOR kinase activation leads to the immunometabolic shift to M1 macrophages that generate pro-inflammatory cytokine by activation of NF-κB and HIF1α signaling. M1-like macrophages increase glycolysis and inflammation through HIF1α and NF-κB signaling pathways. In later phase of infection, M2-like macrophages increase mitochondrial oxidative phosphorylation through AMPK activation. AMPK pathway enhances PGC1α and ERRα activity that is required for autophagy activation through transcriptional and translational regulation. Although the mTOR-HIF1α pathway is essential for initial control of Mtb growth, excessive induction of inflammation seems to be harmful to the host. Similarly, the prolonged activation of AMPK signaling to drive M2-like macrophages may result in the immunosuppression that is detrimental to eradicate intracellular mycobacteria.