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

Abstract

We hypothesised that individuals with immunological sensitisation to Mycobacterium tuberculosis ( Mtb ), conventionally regarded as evidence of latent tuberculosis infection (LTBI), would demonstrate binary responses to preventive therapy (PT), reflecting the differential immunological consequences of the sterilisation of viable infection in those with active Mtb infection versus no Mtb killing in those who did not harbour viable bacilli. We investigated longitudinal whole blood transcriptional profile responses to PT of Interferon gamma release assay (IGRA)-positive tuberculosis contacts and IGRA-negative, tuberculosis-unexposed controls. Longitudinal unsupervised clustering analysis with a subset of 474 most variable genes in antigen-stimulated blood separated the IGRA-positive participants into two distinct subgroups, one of which clustered with the IGRA-negative controls. 117 probes were differentially expressed over time between the two cluster groups, many of them associated with immunological pathways important in mycobacterial control. We contend that the differential host RNA response reflects lack of Mtb viability in the group that clustered with the IGRA-negative unexposed controls, and Mtb viability in the group (1/3 of IGRA-positives) that clustered away. Gene expression patterns in the blood of IGRA-positive individuals emerging during the course of PT, which reflect Mtb viability, could have major implications in the identification of risk of progression, treatment stratification and biomarker development.

Understanding the interaction between cytomegalovirus and tuberculosis in children: The way forward

“…For TB diagnostics, improved approaches for both TB infection and TB disease are required. For TB infection, more advanced assays for pathogen detection, in addition to immunological sensitisation are needed [ 94 , 95 ], as are tools to determine viable bacilli that are likely to cause future disease [ 96 , 97 ]. For TB disease, microbiological evaluations using traditional respiratory specimens require optimisation, and newer diagnostics, using biomarkers in blood and urine, should be applied [ 98 , 99 ].…”

The Variation of Transcriptomic Perturbations is Associated with the Development and Progression of Various Diseases

“…Pulmonary tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis attacking lungs [ 29 ]. In three transcriptome datasets (GSE28623 [ 30 ], GSE153340 [ 31 ], and GSE152532 [ 32 ]), TB patients showed greater VTP values than normal controls ( P < 0.001) ( Figure 2(d) ). Moreover, in GSE152532 and GSE28623 [ 30 ], VTP values likely followed the pattern: active TB > latent TB > normal controls ( Figure 2(d) ).…”

Transcriptional profiles predict treatment outcome in patients with tuberculosis and diabetes at diagnosis and at two weeks after initiation of anti-tuberculosis treatment

“… 32 We have also previously found that metformin has minimal impact on circulating blood transcriptomes, 61 as do TB drugs. 62 Our study was also too small to perform a stratified analysis based on the type of poor outcome, i.e. death, default, treatment failure or recurrence after treatment completion.…”