Longitudinal Plasma Proteomic Profiling Reveals Divergent Immune Responses in Durably Cured and Relapsed Pulmonary Tuberculosis.

: Although clinical biomarkers of tuberculosis (TB) relapse are well characterized, the biological mechanisms underlying different treatment outcomes remain poorly understood. Elucidating these mechanisms may reveal improved biomarkers of long-term treatment outcomes.: We conducted a longitudinal, global proteomic study on 60 participants with active pulmonary TB, half who were durably cured and half who relapsed. Plasma was collected at seven time-points: at treatment initiation (baseline), during therapy, and 52 weeks postbaseline. Samples were analyzed by high-resolution LC-MS/MS.: 2,418 proteins were identified across all samples, with 1,756 being differentially expressed relative to baseline (< 0.05). 956 proteins were differentially abundant between cured and relapsed participants. Relapsed participants showed heightened humoral immunity throughout treatment, as well as upregulated complement activation and HDL particles. Cured participants exhibited elevated recovery-related pathways by week 4, including downregulated epithelial invasion and upregulated oxygen transport.: Heightened humoral and innate immune responses were associated with relapse, whereas recovery signatures were associated with durable cure. Several proteins showed potential as relapse biomarkers and warrant future validation in independent cohorts. These findings advance our understanding of host responses to treatment and provide a basis for developing blood-based biomarkers to identify patients at increased risk of relapse.