Blood Transcriptional Signature of hyperinflammation in HIV-associated Tuberculosis. Homo sapiens

Patients with HIV-associated TB are known to experience systemic hyperinflammation, clinically known as immune reconstitution inflammatory syndrome (IRIS), following the commencement of antiretroviral therapy (ART). No prognostic markers or biomarkers have been identified to date and little is known about the mechanism mediating the hyperinflammation. We recruited a prospective cohort of 63 patients with HIV-associated TB, 33 of whom developed TB-IRIS. Of which transcriptomic profiling was performed using longitudinal whole blood RNA samples from 15 non-IRIS and 17 TB-IRIS patients. Transcriptomic signatures that distinguish patients who would eventually develop IRIS were identified as early as week 0.5 (2-5 days post-ART) and predicted a downstream activation of proinflammatory cytokines. At the peak of IRIS (week 2), transcriptomic signatures were overrepresented by innate receptor signaling pathways including toll-like receptor, IL-1 receptor and TREM-1. Overall design: Patients are classified either as TB-IRIS and non-IRIS and longitudinal samples (week 0, 0.5, 1 and 2) were analyzed. There are a total of 107 samples across all 4 timepoints. For normalization, week 0 samples were baseline transformed to the median of all samples. For all other weeks, samples were baseline transformed either to the median of all samples or to the corresponding week 0 values. Samples 5411298027_F and 5412485008_F do not have a corresponding baseline and were therefore excluded in the analysis for the latter.

已知HIV相关结核病（HIV-associated TB）患者在启动抗逆转录病毒治疗（antiretroviral therapy, ART）后，会出现全身性过度炎症反应，临床将其称为免疫重建炎症综合征（immune reconstitution inflammatory syndrome, IRIS）。截至目前，尚未发现任何可用于预后判断的标志物或生物标志物，学界对介导该过度炎症反应的分子机制仍知之甚少。本研究前瞻性招募了63名HIV相关结核病患者，其中33名发展为结核病相关免疫重建炎症综合征（TB-IRIS）。研究针对15名非IRIS患者与17名TB-IRIS患者的纵向全血RNA样本，开展了转录组谱分析（transcriptomic profiling）。研究早在抗逆转录病毒治疗后第0.5周（即治疗后2-5天）就鉴定出了可区分最终会进展为IRIS的患者的转录组特征，且该特征能够预测促炎细胞因子的下游激活通路。在IRIS发作峰值期（第2周），转录组特征显著富集于固有免疫受体信号通路，包括Toll样受体（toll-like receptor）、IL-1受体以及髓系细胞触发受体1（TREM-1）。本研究整体设计如下：将患者分为TB-IRIS组与非IRIS组，对其纵向采集的第0、0.5、1、2周样本进行分析，所有4个时间点共计纳入107份样本。为完成数据标准化处理，第0周样本以全部样本的中位数为基准进行基线转换；其余各周样本则以全部样本的中位数或对应第0周样本的数值为基准进行基线转换。编号为5411298027_F与5412485008_F的样本无对应基线样本，因此在后续分析中被排除。