Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is a leading cause of death worldwide. Despite decades of research, there is still much to be uncovered regarding the immune response to Mtb infection. Here, we summarize the current knowledge on anti-Mtb immunity, with a spotlight on immune cell amino acid metabolism. Specifically, we discuss L-arginine and L-tryptophan, focusing on their requirements, regulatory roles, and potential use as adjunctive therapy in TB patients. By continuing to uncover the immune cell contribution during Mtb infection and how amino acid utilization regulates their functions, it is anticipated that novel host-directed therapies may be developed and/or refined, helping to eradicate TB.

Immunonutrition as a therapeutic approach is rapidly gaining interest in the fight against infection. Targeting l-arginine metabolism is intriguing, considering this amino acid is the substrate for antimicrobial NO production by macrophages. The importance of l-arginine during infection is supported by the finding that inhibiting its synthesis from its precursor l-citrulline blunts host defense. During the first few weeks following pulmonary mycobacterial infection, we found a drastic increase in l-citrulline in the lung, even though serum concentrations were unaltered. This correlated with increased gene expression of the l-citrulline–generating (i.e., iNOS) and l-citrulline–using (i.e., Ass1) enzymes in key myeloid populations. Eliminating l-arginine synthesis from l-citrulline in myeloid cells via conditional deletion of either Ass1 or Asl resulted in increased Mycobacterium bovis bacillus Calmette-Guérin and Mycobacterium tuberculosis H37Rv burden in the lungs compared with controls. Our data illustrate the necessity of l-citrulline metabolism for myeloid defense against mycobacterial infection and highlight the potential for host-directed therapy against mycobacterial disease targeting this nutrient and/or its metabolic pathway.