Xia Shengfang, An Qi, Lin Rui, Tu Yalan, Chen Zhu, Wang Dongmei
Department of Science and Education Division, Public Health Clinical Center of Chengdu, Chengdu, Sichuan, China.
Front Immunol. 2025 Jun 18;16:1599667. doi: 10.3389/fimmu.2025.1599667. eCollection 2025.
Diagnostic delays in tuberculosis (TB) threaten global control efforts, necessitating early detection of active TB (ATB). This study explores neutrophil extracellular traps (NETs) as key mediators of TB immunopathology to identify NETs-related biomarkers for differentiating ATB from latent TB infection (LTBI).
We analyzed transcriptomic datasets (GSE19491, GSE62525, GSE28623) using differential expression analysis (|log, FC| ≥ 0.585, adj. p < 0.05), immune cell profiling (CIBERSORT), and machine learning (SVM-RFE, LASSO, Random Forest). Regulatory networks and drug-target interactions were predicted using NetworkAnalyst, Tarbase, and DGIdb.
We identified three hub genes (CD274, IRF1, HPSE) showing high diagnostic accuracy (AUC 0.865-0.98, sensitivity/specificity >80%) validated through ROC/precision-recall curves. IRF1 and HPSE correlated with neutrophil infiltration (r > 0.6, p < 0.001), suggesting roles in NETosis. FOXC1, GATA2, and hsa-miR-106a-5p emerged as core regulators, and 46 candidate drugs (e.g., PD-1 inhibitors, heparin) were prioritized for repurposing.
CD274, IRF1, and HPSE represent promising NETs-derived diagnostic biomarkers for ATB. Their dual roles in neutrophil-mediated immunity highlight therapeutic potential, though drug predictions require preclinical validation. Future studies should leverage spatial omics and CRISPR screening to elucidate mechanistic pathways.
结核病（TB）诊断延误威胁全球防控工作，因此有必要早期检测活动性结核病（ATB）。本研究探讨中性粒细胞胞外陷阱（NETs）作为结核病免疫病理学的关键介质，以识别与NETs相关的生物标志物，用于区分ATB与潜伏性结核感染（LTBI）。
我们使用差异表达分析（|log₂FC|≥0.585，校正p<0.05）、免疫细胞谱分析（CIBERSORT）和机器学习（支持向量机-递归特征消除法、套索回归、随机森林）分析转录组数据集（GSE19491、GSE62525、GSE28623）。使用NetworkAnalyst、Tarbase和DGIdb预测调控网络和药物-靶点相互作用。
我们鉴定出三个枢纽基因（CD274、IRF1、HPSE），通过ROC/精确召回率曲线验证，其显示出较高的诊断准确性（AUC为0.865 - 0.98，灵敏度/特异性>80%）。IRF1和HPSE与中性粒细胞浸润相关（r>0.6，p<0.001），提示其在NETosis中的作用。FOXC1、GATA2和hsa-miR-106a-5p成为核心调节因子，46种候选药物（如PD-1抑制剂、肝素）被优先考虑用于重新利用。
CD274、IRF1和HPSE代表了有前景的源自NETs的ATB诊断生物标志物。它们在中性粒细胞介导的免疫中的双重作用突出了治疗潜力，尽管药物预测需要临床前验证。未来的研究应利用空间组学和CRISPR筛选来阐明作用机制途径。
