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.

中文翻译：

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宿主对结核病预防治疗的转录反应区分了 IGRA 阳性个体的两个亚组


摘要：我们假设对结核分枝杆菌 (Mtb) 具有免疫敏感性的个体（通常被视为潜伏性结核感染 (LTBI) 的证据）将表现出对预防性治疗 (PT) 的二元反应，反映了对活感染进行灭菌的不同免疫学后果。那些患有活跃结核分枝杆菌感染的人与那些没有活杆菌的人没有杀灭结核分枝杆菌。我们研究了干扰素γ释放测定（IGRA）阳性结核病接触者和IGRA阴性、结核病未暴露对照对PT的纵向全血转录谱反应。对抗原刺激血液中 474 个最可变基因的子集进行纵向无监督聚类分析，将 IGRA 阳性参与者分为两个不同的亚组，其中一组与 IGRA 阴性对照聚类。随着时间的推移，两个簇组之间有 117 个探针出现差异表达，其中许多探针与分枝杆菌控制中重要的免疫途径相关。我们认为，宿主 RNA 反应的差异反映了与 IGRA 阴性未暴露对照聚集的组中缺乏 Mtb 活力，而远离聚集的组（IGRA 阳性对照的 1/3）则缺乏 Mtb 活力。 PT 过程中出现的 IGRA 阳性个体血液中的基因表达模式反映了结核分枝杆菌的生存能力，可能对疾病进展风险的识别、治疗分层和生物标志物的开发产生重大影响。