Development and evaluation of innovative tuberculosis diagnostics and study of the cross-impact of Sars-CoV-2 pandemic

Résumé

Tuberculosis (TB) remains one of the deadliest infectious diseases in the world. Given the limitations of existing sputum-based diagnostic tests in terms of specimen collection and diagnostic performance, the World Health Organization (WHO) has declared an urgent need to find new non-sputum-based tests for the diagnosis and monitoring of treatment efficacy of TB.The objective of this thesis was to evaluate and develop new TB diagnostic tools in accordance with WHO criteria for sensitivity and specificity for the diagnosis and treatment of TB. Thus, we evaluated host biomarkers based on a simplified and more rapid approach.Firstly, we evaluated the host gene signature RISK6. The latter was assessed by quantitative real-time PCR and the performance of the assay estimated by analysing the area under the receiver operating curve (AUC ROC) on active TB patients (ATB), TB infection patients (TBI), and healthy donors (HD). The performance of RISK6 in discriminating TBI from HDs achieved an AUC of 0.94, a sensitivity of 90.9% and a specificity of 87.8%, thus meeting the WHO criteria for a non-sputum-based TB test.Secondly, of 7 host protein biomarkers evaluated from plasma using Luminex assay, we identified a signature of 4 proteins discriminating between different clinical groups (ATB, TBI and HD) recruited in Madagascar.The signature (CLEC3B-ECM1-IP10-SELL) allows to discriminate TBA from HD with an AUC of 0.96, a sensitivity of 95.6% and a specificity of 91.7%. This signature also enables us to differentiate between patients who respond rapidly to TB treatment and patients who respond late to their treatments with an AUC of 0.87, a sensitivity of 83.3% and a specificity of 84%.Finally, we developed and evaluated a serodiagnostic tool for the detection of specific anti-SARS-COV-2 antibodies based on Luminex technology. Using this tool, we showed that SARS-CoV-2 virus circulated strongly in the Madagascar cohort of TB patients and their contacts between December 2020 and December 2021 with a seroprevalence of 77.16% in IgG and 51.84% in IgM. When comparing seroprevalence data with TB progression, no significant difference was observed for the anti-SARS-CoV-2 humoral response between patients who progressed to TB and non-progressors in the contact cohort studied.The results of this thesis provide strong evidence that non-sputum-based tests are promising alternatives to improve TB diagnosis and treatment monitoring. These results support efforts to translate such tools into simplified, less expensive and more accessible tests, ensuring rapid and early detection of TB infection and monitoring of response to TB treatment.

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