Targeting Tryptophan Metabolism for Tuberculosis Biomarkers and Host-Directed Therapy

Greater understanding of the role of tryptophan metabolism in the immune response to tuberculosis (TB) has provided promising avenues to explore new diagnostic and therapeutic modalities. Animal and human studies have demonstrated that host indoleamine 2,3-dioxygenase 1 (IDO1) is upregulated in response to infection with Mycobacterium tuberculosis, resulting in increased tryptophan metabolism to kynurenine. In TB disease, this is evidenced by elevation of the plasma kynurenine to tryptophan ratio, which is reversed with effective TB treatment, thus showing utility as a potential diagnostic and therapeutic biomarker. Kynurenine and downstream metabolites promote an immunosuppressive microenvironment in TB granulomas, which may facilitate immune evasion. IDO inhibition in nonhuman primates has highlighted its potential role as host-directed therapy by demonstrating increased T-cell trafficking to the granuloma core, reduced bacterial burden, and decreased immunopathology. To realize the potential of exploiting the tryptophan to kynurenine metabolic pathway, innovative biomarker and host-directed therapy trials are needed.