Early tuberculosis treatment remodels blood mRNA and small RNA, and a baseline host signature is associated with early culture conversion

Tuberculosis (TB) treatment monitoring relies on sputum-based microbiological assays, which are slow and provide limited insight into the host response. Blood-based biomarkers could offer rapid and minimally invasive treatment monitoring. We performed an integrative multi-omics analysis of paired whole-blood samples collected at baseline and four weeks after treatment initiation across three South African cohorts. A meta-analysis combined RNA sequencing data from GSE89403 (86 pairs) and a prospective cohort (11 pairs), with directional concordance assessed in an independent microarray cohort, GSE31348 (27 pairs). In the prospective cohort, small RNA sequencing profiled microRNAs (miRNAs) and tRNA-derived fragments (tRFs). In GSE89403 (n = 76), a k-top scoring pairs signature (EARLY5) was developed using leave-one-out cross-validation to predict week-4 sputum culture conversion from baseline samples. The meta-analysis identified 63 concordantly regulated genes. These changes reflected attenuation of neutrophil, inflammatory and complement programs, and deconvolution showed decreased neutrophils with increased T-cell and NK-cell populations. Seven miRNAs and eight nuclear-encoded tRFs changed during treatment, including erythroid-associated miR-144, with computationally identified candidate interactions involving complement genes. EARLY5 identified participants who converted by week 4 with a cross-validated AUC of 0.76 and remained associated with conversion after adjustment for baseline bacterial burden in logistic regression and performed comparably to existing TB signatures. Early TB treatment induces coordinated remodeling of blood mRNA and small RNA profiles. Baseline host transcriptional profiles were associated with early culture conversion after accounting for bacterial burden, supporting further evaluation in independent cohorts.