Project description:We hypothesized that individuals with immunological sensitization to Mycobacterium tuberculosis (Mtb), conventionally regarded as evidence of latent tuberculosis infection (LTBI), would demonstrate binary responses to preventive therapy. This would reflect the differential immunological consequences of the sterilization of viable infection in those with an active Mtb infection versus no Mtb killing in those who, despite T cell recognition of Mtb antigens, did not harbor viable Mtb bacilli. We investigated the blood transcriptional profiles of 18 individuals with a positive IGRA result and known recent exposure to an index person with isoniazid and rifampicin susceptible pulmonary tuberculosis, at baseline, 2 weeks after initiating combined rifampicin/isoniazid (RH) preventive therapy and at treatment completion. Healthy control volunteers with no history of TB exposure and negative IGRA results were also included. RNA from unstimulated and M. tuberculosis peptide stimulated whole blood (from QuantiFERON TB1 and TB2 tubes) was measured using Agilent microarrays. A set of 474 genes showed the greatest interpersonal and temporal expression variability in antigen-stimulated blood. By performing longitudinal unsupervised clustering analysis with the subset of most variable genes, the IGRA+ participants were separated into two distinct groups. The IGRA-negative controls clustered within one of these groups suggesting that, in contrast to the other subgroup of IGRA+ individuals, RH had no discernible effect in this subgroup. 117 genes were significantly differentially expressed over time between these two groups, with the majority of them associated with immunological pathways known to be important in mycobacterial control. We contend that the different host RNA response reflects lack of Mtb viability in the group that clustered with the IGRA- unexposed healthy controls, and Mtb viability in the one that clustered away. Gene expression patterns in the blood of IGRA+ individuals emerging during the course of RH treatment which reflect Mtb viability could have major implications in the identification of risk of progression/reactivation, treatment stratification and clinical trials for LTBI therapy.

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Host transcriptional response to TB preventive therapy differentiates two sub-groups of IGRA-positive individuals

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