Sutherland, J. S. | Search bioRxiv

bioRxiv2026

Associations Between QuantiFERON-TB Gold Plus IFNγ Concentrations and Progression to Symptomatic Tuberculosis in Global High-Burden TB Settings

IntroductionPredictive biomarkers for symptomatic tuberculosis (TB) progression would transform targeted prevention efforts. Although interferon-gamma release assays (IGRAs), including QuantiFERON(R) TB-Gold Plus (QFT-Plus), have been studied for this purpose, systematic evaluation of the QFT-Plus TB1 and TB2 Interferon-Gamma (IFN{gamma}) concentrations remains limited, particularly in high-burden TB settings. MethodsBaseline TB1 and TB2 IFN{gamma} concentrations from 5,259 participants in TB-endemic regions were analyzed in relation to subsequent TB outcomes over a median of 525 days follow-up. Participants were categorized as controls (no TB), suspected TB (no microbiological confirmation), or laboratory-confirmed TB, including a subset meeting a stringent case definition ([≥]2 positive microbiologic tests). Associations between baseline IFN{gamma} concentrations and progression to symptomatic TB were assessed. ResultsIn the full cohort (IGRA+/-participants), baseline TB2 IFN{gamma} concentrations were significantly higher compared to controls among participants who developed suspected TB (p=0.01), laboratory-confirmed TB (p=0.01), or met the stringent case definition (p<0.0001). In IGRA+ participants, baseline TB2 concentrations were significantly higher than controls in suspected (p=0.01) and laboratory-confirmed (p=0.02) groups. Associations with baseline TB1 IFN{gamma} concentrations and TB progression were observed for participants meeting the stringent case definition within the full cohort (p=0.009). Among stringent definition cases, TB2 concentrations achieved an area under the Receiver Operating Characteristic curve of 0.84, with a sensitivity of 80% and specificity of 78%. ConclusionsQuantitative IFN{gamma} concentrations from QFT-Plus, particularly TB2, were associated with progression to symptomatic TB, met or exceeded WHO-recommended sensitivity and specificity thresholds for predictive biomarkers, and may support biomarker-based stratification in TB clinical research. SummaryIn an exploratory analysis from a global tuberculosis (TB) epidemiology study, higher QuantiFERON-TB Gold Plus IFN{gamma} concentrations were associated with progression to symptomatic TB and met WHO predictive biomarker thresholds, supporting their potential value for risk stratification in TB research.

immunology↗

bioRxiv2022

Neutrophil degranulation, NETosis and platelet degranulation pathway genes are co-induced in whole blood up to six months before tuberculosis diagnosis

Mycobacterium tuberculosis (M.tb) causes tuberculosis (TB) and remains one of the leading causes of mortality due to an infectious pathogen. Host immune responses have been implicated in driving the progression from infection to severe lung disease. We analyzed longitudinal RNA sequencing (RNAseq) data from the whole blood of 74 TB progressors whose samples were grouped into four six-month intervals preceding diagnosis (the GC6-74 study). We additionally analyzed RNAseq data from an independent cohort of 90 TB patients with positron emission tomography-computed tomography (PET-CT) scan results which were used to categorize them into groups with high and low levels of lung damage (the Catalysis TB Biomarker study). These groups were compared to non-TB controls to obtain a complete whole blood transcriptional profile for individuals spanning from early stages of M.tb infection to TB diagnosis. The results revealed a steady increase in the number of genes that were differentially expressed in progressors at time points closer to diagnosis with 278 genes at 13-18 months, 742 at 7-12 months and 5,131 detected 1-6 months before diagnosis and 9,205 detected in TB patients. A total of 2,144 differentially expressed genes were detected when comparing TB patients with high and low levels of lung damage. There was a large overlap in the genes upregulated in progressors 1-6 months before diagnosis (86%) with those in TB patients. A comprehensive pathway analysis revealed a potent activation of neutrophil and platelet mediated defenses including neutrophil and platelet degranulation, and NET formation at both time points. These pathways were also enriched in TB patients with high levels of lung damage compared to those with low. These findings suggest that neutrophils and platelets play a critical role in TB pathogenesis, and provide details of the timing of specific effector mechanisms that may contribute to TB lung pathology. Author summaryMycobacterium tuberculosis (M.tb) causes tuberculosis (TB) and remains one of the leading causes of mortality due to an infectious pathogen. Human immune responses must be balanced to inhibit disease progression while limiting self-damage, however in defense against M.tb host responses have been implicated in lung damage and in driving progression of M.tb infection to severe lung disease. The identification of immune responses that are activated during the development of TB could provide potential targets for interventions that might suppress disease progression, and possibly limit tissue damage. Here we identify a subset of genes that function in several biological processes that are strongly activated in the late stages of TB development and in TB patients. The proteins encoded by these genes are known to degrade lung tissue and contribute to severe lung disease.

genomics↗