Abstract
Immune metabolic regulation shapes the host-pathogen interaction during infection with Mycobacterium tuberculosis (Mtb), the pathogen of human tuberculosis (TB). Several immunometabolites generated by metabolic remodeling in macrophages are implicated in innate immune protection against Mtb infection by fine-tuning defensive pathways. Itaconate, produced by the mitochondrial enzyme immunoresponsive gene 1 (IRG1), has antimicrobial and anti-inflammatory effects, restricting intracellular mycobacterial growth. L-arginine, a component of the urea cycle, is critical for the synthesis of nitric oxide (NO) and is implicated in M1-mediated antimycobacterial responses in myeloid cells. L-citrulline, a by-product of NO production, contributes to host defense and generates L-arginine in myeloid cells. In arginase 1-expressing cells, L-arginine can be converted into ornithine, a polyamine precursor that enhances autophagy and antimicrobial protection against Mtb in Kupffer cells. Gamma-aminobutyric acid (GABA), a metabolite and neurotransmitter, activate autophagy to induce antimycobacterial host defenses. This review discusses the recent updates of the functions of the three metabolites in host protection against mycobacterial infection. Understanding the mechanisms by which these metabolites promote host defense will facilitate the development of novel host-directed therapeutics against Mtb and drug-resistant bacteria.
Highlights
Metabolites function as innate immune effectors against intracellular bacterial infections, including Mycobacterium tuberculosis (Mtb), the primary pathogen of human tuberculosis (TB)
A significant advance occurred with identifying itaconate, produced by immunoresponsive gene 1 (Irg1) enzymatic activity, in the growth inhibition of mycobacteria possessing isocitrate lyase [1, 2]
An earlier study showed that L-arginine (Arg) metabolism is closely related to bacteriostatic activity in macrophages [5]
Summary
Metabolites function as innate immune effectors against intracellular bacterial infections, including Mycobacterium tuberculosis (Mtb), the primary pathogen of human tuberculosis (TB). Another metabolite of the L-Arg metabolic pathway, is mainly produced by Kupffer cells in the liver and participates in host defense by activating autophagy [7]. G-aminobutyric acid (GABA), a metabolite and neurotransmitter, activates autophagy to induce innate host defenses against intracellular bacteria, including mycobacteria and salmonella [8]. We focus on the roles and mechanisms by which three metabolites— itaconate, Arg, and GABA—enhance host defenses in macrophages during Mtb infection.
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