L-Arginine Synthesis from L-Citrulline in Myeloid Cells Drives Host Defense against Mycobacteria In Vivo

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-Guerin 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.