Unravelling the transcriptome of the human tuberculosis lesion and its clinical implications

The granuloma is a complex structure, contributing to the overall spectrum of tuberculosis (TB). We characterised 44 fresh human pulmonary TB lesion samples from 13 patients (drug-sensitive and multi-drug resistant TB) undergoing therapeutic surgery using RNA-Sequencing. We confirmed a clear separation between the granuloma and adjacent non-lesional tissue, with the granuloma samples consistently displaying an increased inflammatory profile despite heterogeneity. Using weighted correlation network analysis, we identified 17 transcriptional modules associated with granulomata and demonstrated a gradient of immune-related transcript abundance according to the granuloma’s spatial organization. Furthermore, we associated the modular transcriptional signature of the TB granuloma with clinical surrogates of treatment efficacy and TB severity. We show that in patients with severe disease, the IFN/cytokine signalling and neutrophil degranulation modules were overabundant, while tissue organization and metabolism modules were under-represented. Our findings provide evidence of a relationship between clinical parameters, treatment response and immune signatures at the infection site. A total of 48 total-RNA samples underwent RNA-seq from 14 patients undergoing therapeutic surgery from their pulmonary tuberculosis (TB) (Discovery Set). Total RNA was extracted from removed human tuberculosis granuloma biopsies (Center of the Lesion, Internal Wall, and External Wall) and surrounding non-lesional (NL) lung parenchyma tissue (as a control). Patients were matched according to sex (7 males and 7 females), and by their drug sensitivity to chemotherapy (6 drug-sensitive, 6 multi-drug resistant, and 2 extensively drug-resistant TB). Epidemiological, general clinical, TB-related and microbiological aspects are included.