Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Stellenbosch University, Cape Town, South Africa.
DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, Stellenbosch University, Cape Town, South Africa.
PLoS One. 2022 Dec 1;17(12):e0278295. doi: 10.1371/journal.pone.0278295. eCollection 2022.
Mycobacterium tuberculosis (M.tb) causes tuberculosis (TB) and remains one of the leading causes of mortality due to an infectious pathogen. Host immune responses have been implicated in driving the progression from infection to severe lung disease. We analyzed longitudinal RNA sequencing (RNAseq) data from the whole blood of 74 TB progressors whose samples were grouped into four six-month intervals preceding diagnosis (the GC6-74 study). We additionally analyzed RNAseq data from an independent cohort of 90 TB patients with positron emission tomography-computed tomography (PET-CT) scan results which were used to categorize them into groups with high and low levels of lung damage (the Catalysis TB Biomarker study). These groups were compared to non-TB controls to obtain a complete whole blood transcriptional profile for individuals spanning from early stages of M.tb infection to TB diagnosis. The results revealed a steady increase in the number of genes that were differentially expressed in progressors at time points closer to diagnosis with 278 genes at 13-18 months, 742 at 7-12 months and 5,131 detected 1-6 months before diagnosis and 9,205 detected in TB patients. A total of 2,144 differentially expressed genes were detected when comparing TB patients with high and low levels of lung damage. There was a large overlap in the genes upregulated in progressors 1-6 months before diagnosis (86%) with those in TB patients. A comprehensive pathway analysis revealed a potent activation of neutrophil and platelet mediated defenses including neutrophil and platelet degranulation, and NET formation at both time points. These pathways were also enriched in TB patients with high levels of lung damage compared to those with low. These findings suggest that neutrophils and platelets play a critical role in TB pathogenesis, and provide details of the timing of specific effector mechanisms that may contribute to TB lung pathology.
结核分枝杆菌（M.tb）引起结核病（TB），仍然是导致死亡的主要传染病病原体之一。宿主免疫反应被认为是导致从感染到严重肺部疾病进展的原因。我们分析了 74 名结核病进展者的全血纵向 RNA 测序（RNAseq）数据，这些样本在诊断前分为四个六个月间隔（GC6-74 研究）。我们还分析了来自 90 名结核病患者的独立 RNAseq 数据，这些患者的正电子发射断层扫描-计算机断层扫描（PET-CT）扫描结果用于将他们分为肺部损伤水平高和低的两组（Catalysis TB Biomarker 研究）。将这些组与非结核病对照进行比较，以获得从早期 M.tb 感染到结核病诊断的个体的完整全血转录谱。结果显示，随着接近诊断的时间点，进展者中差异表达基因的数量稳步增加，在 13-18 个月时有 278 个基因，在 7-12 个月时有 742 个基因，在 1-6 个月前诊断时有 5131 个基因，在结核病患者中有 9205 个基因。当比较肺部损伤水平高和低的结核病患者时，共检测到 2144 个差异表达基因。在诊断前 1-6 个月的进展者中上调的基因与结核病患者中有 86%的基因重叠。全面的途径分析显示，中性粒细胞和血小板介导的防御作用被强烈激活，包括中性粒细胞和血小板脱颗粒，以及在两个时间点形成 NET。与肺部损伤水平低的患者相比，这些途径在肺部损伤水平高的结核病患者中也更为丰富。这些发现表明，中性粒细胞和血小板在结核病发病机制中发挥着关键作用，并提供了可能导致结核病肺部病理学的特定效应机制的时间细节。
