A novel glutamine metabolism inhibitor improves phagocytic abilities of macrophages by reprogramming glutathione metabolism 2956

Abstract Description Mycobacterium tuberculosis (Mtb) alters host metabolic patterns and inhibits host immunity through poorly understood mechanisms. Glutamine (Gln) metabolism upregulation promotes immune tolerance and immunosuppression in several infectious diseases and cancers. We reported that JHU083-mediated Gln metabolism inhibition drives immunomodulatory changes in Mtb-infected lungs and reduces bacterial burden. We hypothesize that JHU083-mediated Gln inhibition improves the antibacterial activity of macrophages. Untargeted metabolomics of JHU083-treated macrophages revealed (1) significantly lower levels of Gln and (2) depletion of glutathione metabolism metabolites such as oxidized glutathione. As elevated oxidized glutathione-related metabolites are a strong indicator of cellular oxidative stress, JHU083-mediated depletion of these metabolites identifies a hitherto unidentified role of Gln metabolism inhibition in containing cellular oxidative stress. Accordingly, JHU083-treated macrophages exhibited significantly higher phagocytic activity than untreated macrophages. Future metabolite tracing experiments will decipher the precise mechanism driving this effect. In conclusion, JHU083, a Gln metabolism inhibitor prodrug, alleviates cellular oxidative stress in macrophages, ultimately improving their phagocytic activities and reducing intracellular bacterial burden. Hence, we have identified a new metabolic mechanism that drives the antibacterial activity of JHU083 at least ex-vivo. Funding Sources JHU-TRAC development award grant NIH grant P30AI18436 NIH R01AI155602 NIH R01CA226765 Bloomberg-Kimmel Institute for Cancer Immunotherapy Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)