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

Background: 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. Methods: 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. Results: 2,418 proteins were identified
across all samples, with 1,756 being differentially expressed relative
to baseline (p < 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. Conclusions: 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.