Analysis of immunological resistance to primary <i>Mycobacterium tuberculosis</i> infection in humans

Abstract Background Despite recent advances in diagnosis and treatment, tuberculosis (TB) remains a major infectious disease killer in resource-poor settings. Strategies to prevent Mycobacterium tuberculosis (Mtb) infection are urgently required. By characterising natural protective immunity to Mtb infection we aimed to identify correlates of protection to guide vaccine development and other immune based therapies. Methods Two groups of Mtb-exposed contacts of TB patients were recruited in The Gambia and assessed for Mtb infection status using either tuberculin skin test (TST) reactivity at baseline and 3 months or QuantiFERON (QFT) reactivity at baseline and 6 months. For both groups, converters were defined as having a negative test at baseline and a positive one at follow-up, while those with a negative test at both time-points were defined as non-converters (Mtb resisters). Participants were analysed using RNA-sequencing and plasma Mtb proteome IgA and IgG arrays. Results Several genes were found to be differentially expressed at baseline between the groups prior to any signs of infection by current tests. Modular analysis revealed a distinct B cell gene signature in TST non-converters compared to converters (at q &lt; 10 -6 , AUC &gt; 0.7), which was only present in the most highly exposed group. Interestingly, when infection status was defined by QFT, enrichment of Type I IFN and antiviral gene signatures was observed. Plasma IgG and IgA antibody reactivity across the entire Mtb proteome showed the best differentiation in individuals with the highest exposure. An AUC of 1.0 (q&lt;10 -3 ) was observed for IgA reactivity to Rv0134 and an AUC of 0.98 for IgA reactivity to both Rv0629c and Rv2188c (all lower in TST non-converters). IgG reactivity to Rv3223c resulted in an AUC of 0.96 (q &lt; 10 -4 ) and was again lower in TST non-converters. The highest AUC for those with lower Mtb exposure were 0.84 (Rv2411c) for IgA and 0.83 (Rv2131c) for IgG. Conclusions These data provide insight into the early protective response to Mtb infection and possible avenues for novel therapeutic strategies to prevent Mtb infection.