Changes in transcript, metabolite and antibody reactivity during the early protective immune response in humans to Mycobacterium tuberculosis infection

BACKGROUND: Strategies to prevent Mycobacterium tuberculosis (Mtb) infection are urgently required. This study aimed to identify correlates of protection against early Mtb infection. METHODS: Two groups of Mtb-exposed contacts of TB patients were recruited and classified according to their Mtb infection status using Tuberculin skin test (TST; cohort 1) or QuantiFERON (QFT; cohort 2. A negative reading at baseline with a positive reading at follow-up classified TST or QFT converters and a negative reading at both time-points classified TST or QFT non-converters. RNA-sequencing, Mtb proteome arrays (IgG and IgA) and metabolic profiling was performed. RESULTS: Several genes were found to be differentially expressed at baseline between converters and non-converters prior to any signs of infection by current tests. Gene set enrichment analysis revealed a distinct B cell gene signature in TST non-converters compared to converters. When infection status was defined by QFT, enrichment of Type I IFN and antiviral gene signatures was observed. A remarkable AUC of 1.0 was observed for IgA reactivity to Rv0134 and an AUC of 0.98 for IgA reactivity to both Rv0629c and Rv2188c. IgG reactivity to Rv3223c resulted in an AUC of 0.96 and was markedly higher compared to TST non-converters. We also identified several differences in metabolite profiles, including changes in biomarkers of inflammation, fatty acid metabolism, and bile acids. Pantothenate (Vitamin B5) was significantly increased in TST non-converters compared to converters at baseline (q=0.0060). CONCLUSIONS: These data provide new insights into the early protective response to Mtb infection and possible avenues to interfere with Mtb infection including Vitamin B5 supplementation.