Neutrophil-specific transcriptomic profiling reveals a novel signature for active tuberculosis diagnosis

Tuberculosis remains a leading cause of mortality worldwide. Rapid and accurate diagnosis of active tuberculosis (ATB) is critical for its effective treatment and disease control. However, current sputum-based detection methods have limited diagnostic coverage for ATB, resulting in missed cases and treatment delay. In this study, we performed neutrophil RNA sequencing (RNA-seq) to identify ATB-specific transcriptional signatures. Through integrated analysis of differentially expressed genes (DEGs) across 173 samples (67 ATB, 42 latent tuberculosis infection [LTBI], and 64 healthy controls [HC]), followed by quantitative Real-time polymerase chain reaction (qPCR) validation using 141 samples (31 ATB, 53 LTBI, 57 HC). A novel 4-gene neutrophil-derived tuberculosis signature (neu-TB) was screened by Lasso model prediction, and further evaluation were performed in two independent cohorts ( n = 332). The signature achieved exceptional discrimination between ATB and LTBI (area under curve [AUC] = 0.975; 95% confidence interval [CI]: 0.949-1.000; P n = 141) and validated by qPCR in two independent cohorts (total n = 332), achieving 93% sensitivity/88% specificity in distinguishing active TB from latent infection and non-TB controls.