Untargeted metabolomics analysis reveals Mycobacterium tuberculosis strain H37Rv specifically induces tryptophan metabolism in human macrophages.

Background: Tuberculosis (TB) caused by Mycobacterium tuberculosis (M. tb) remains a global health issue. The characterized virulent M. tb H37Rv, avirulent M. tb H37Ra and BCG strains are widely used as reference strains to investigate the mechanism of TB pathogenicity. Here, we attempted to determine metabolomic signatures associated with the Mycobacterial virulence in human macrophages through comparison of metabolite profile in THP-1-derived macrophages following exposure to the M. tb H37Rv, M. tb H37Ra and BCG strains.

Results: Our findings revealed remarkably changed metabolites in infected macrophages compared to uninfected macrophages. H37Rv infection specifically induced 247 differentially changed metabolites compared to H37Ra or BCG infection. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed H37Rv specifically induces tryptophan metabolism. Moreover, quantitative PCR (qPCR) results showed that indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) which converts the tryptophan to a series of biologically second metabolites were up-regulated in H37Rv-infected macrophages compared to H37Ra- or BCG-infected macrophages, confirming the result of enhanced tryptophan metabolism induced by H37Rv infection. These findings indicated that targeting tryptophan (Trp) metabolism may be a potential therapeutic strategy for pulmonary TB.

Conclusions: We identified a number of differentially changed metabolites that specifically induced in H37Rv infected macrophages. These signatures may be associated with the Mycobacterial virulence in human macrophages. The present findings provide a better understanding of the host response associated with the virulence of the Mtb strain.