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.
Highlights
AMP-activated protein kinase (AMPK) is an essential metabolic sensor that responds to increases in the cellular adenosine monophosphate (AMP) to adenosine triphosphate (ATP) ratio (AMP:ATP) by activating catabolic pathways for energy production
Since its discovery as a pivotal regulator of intracellular bioenergetics, AMPK has emerged as a central coordinator of a variety of biological responses, including autophagy, inflammation, and metabolic reprogramming during mycobacterial infection (Shi et al, 2016; Riffelmacher et al, 2018)
The functions of AMPK are diametrically opposed by those of mammalian target of rapamycin (mTOR), and the balance of the activation of both kinases is reflected in the signaling pathways that converge on host defense in host cells against Mycobacterium tuberculosis (Mtb) infection (Yang et al, 2014)
Summary
AMP-activated protein kinase (AMPK) is an essential metabolic sensor that responds to increases in the cellular adenosine monophosphate (AMP) to adenosine triphosphate (ATP) ratio (AMP:ATP) by activating catabolic pathways for energy production. In addition to the roles described above, emerging evidence suggests that AMPK is involved in the activation of antimicrobial immunity and immunopathologic responses during mycobacterial infection through its interaction with other signaling pathways (Yang et al, 2014; Ong et al, 2015).
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