Friday, May 9, 2025
5/9/2025
Type II arginase and tuberculosis pathogenesis - Abstract The high mortality and morbidity of tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (Mtb), calls for development of novel adjunct host-directed therapies (HDTs) to improve treatment outcome and restrict the emergence of multi-drug-resistant Mtb strains. Knowledge of immunometabolism offers new opportunities for controlling this deadly disease. We and others have characterized immunometabolic changes in multiple animal models of TB and found that metabolic remodeling to the HIF-1-mediated Warburg effect is a general response of host immune cells to Mtb infection. Through detailed analysis of immunometabolic dynamics of the macrophage response to Mtb infection, we discovered that M1-like polarization at initial stages of infection is accompanied by upregulation of ARG2, a type II arginase located in mitochondria. Given the critical roles that mitochondria play in mediating the signaling and metabolic pathways during macrophage activation, the upregulation of mitochondrial ARG2 suggests a little-studied role of this enzyme in M1-like polarization. Indeed, macrophages from Arg2 KO mice showed a diminished proinflammatory response and dysregulated mitochondrial dynamics. The identification of arginine metabolism-associated pathways, as well as upregulation of a related set of genes that include Arg2, using metabolomics and transcriptomics studies of Mtb-infected mouse lungs, also indicate that ARG2-mediated arginine and/or ornithine metabolism is an important regulator of host immunity to control Mtb infection in vivo. Based on these observations, we hypothesize that mitochondrial ARG2 activity contributes to M1-like polarization by regulating mitochondria dynamics and functions, including generation of signaling molecules, activation of signaling networks, and changes in mitochondrial metabolism to meet the biosynthetic and bioenergetic demands of activating macrophages. We will test the hypothesis 1) by delineating ex vivo effects of ARG2-mediated arginine metabolism on mitochondrial biology and macrophage polarization, using multiple approaches/assays that include stable isotope tracing metabolomics; and 2) by characterizing the role of ARG2-mediated arginine/ornithine metabolism in regulating the expression of innate and adaptive immunity during Mtb infection in vivo. We will also test an adjunct HDT through arginine or ornithine supplementation to improve infection outcome. We expect to aid the development of urgently needed adjunct HDTs with dietary supplementation of arginine/ornithine that should help clear the pathogen at an early stage of infection, prevent reactivation from a latent infection, and/or shorten the duration of antibiotic therapy.
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