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.