Glutamine Is Required for M1-like Polarization of Macrophages in Response to Mycobacterium tuberculosis Infection

Macrophages play essential roles in determining the progression and final outcome of human infection by Mycobacterium tuberculosis. While upregulation of hypoxia-inducible-factor 1 (HIF-1) and a metabolic reprogramming to the Warburg Effect-like state are known to be critical for immune cell activation in response to M. tuberculosis infection, our overall knowledge about the immunometabolism of M1-like macrophages is poor. Using widely targeted small-metabolite screening, stable isotope tracing metabolomics, and pharmacological and genetic approaches, we report that, in addition to enhanced glucose catabolism by glycolysis, glutamine is utilized as an important carbon and nitrogen source for the generation of biosynthetic precursors, signaling molecules, and itaconate in M. tuberculosis-induced M1-like macrophages. Recognizing this novel contribution of glutamine to the immunometabolic properties of M. tuberculosis-infected macrophages may facilitate the development of treatments for tuberculosis and stimulate comparable studies with other pathogen-macrophage interactions.