Abstract
BACKGROUND: Tuberculosis (TB) continues to be a major global health challenge, with difficulties in distinguishing active TB (ATB) from latent TB infection (LTBI) and identifying early biomarkers for diagnosis. METHODS: This study integrated single-cell RNA sequencing (scRNA-seq) and bulk transcriptome analysis to systematically characterize the immune landscape of peripheral blood mononuclear cells (PBMCs) from patients with ATB, LTBI, and healthy controls (HC). The goal was to identify novel diagnostic biomarkers and elucidate the immune mechanisms driving TB progression. RESULTS: Analysis of PBMCs scRNA-seq data from 3 ATB patients, 3 LTBI individuals, and 2 HC subjects revealed an immune imbalance in ATB characterized by monocyte/platelet enrichment and lymphocyte depletion. Differential expression analysis uncovered a triad imbalance involving inflammation, metabolism, and structural remodeling during TB infection. The Wnt pathway was significantly downregulated during progression from LTBI to ATB. Subpopulation analysis of monocytes demonstrated activation of interferon and inflammatory pathways across all monocyte subsets in ATB patients, with functional heterogeneity observed. Pseudotime trajectory analysis indicated that monocyte differentiation from classical to non-classical subsets was accompanied by a phenotypic shift from pro-inflammatory to immune surveillance. By integrating these findings with bulk RNA-seq from a discovery cohort (n = 84), 26 core genes were identified. Four genes (GBP5, FLVCR2, IGF2BP3, PSTPIP2) showed excellent diagnostic performance in independent validation (n = 82) and test (n = 108) cohorts. CONCLUSION: Our findings reveal that dynamic monocyte reprogramming and Wnt pathway dysregulation are key features of tuberculosis progression. The identified high-potential diagnostic biomarkers may provide new insights for early diagnosis and targeted intervention of tuberculosis. CLINICAL TRIAL NUMBER: Not applicable. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12879-026-12805-w.