Targeted transcriptomic analyses of Tuberculosis treatment response and outcomes in The Gambia

Ismaila L. Manneh^1*Fatoumatta Darboe^1,2Haddijatou Jobe¹Binta Sarr¹Ousainou Cham¹Olumuyiwa Adesina Owolabi¹Brezesky Kotanmi³Andrea Rachow⁴Salome Charalambous⁵Kathrin Held^6,7,8,9Hazel Marguerite Dockrell¹⁰Jayne S Sutherland¹¹

• ¹Vaccines and Immunity Theme, Medical Research Council Unit The Gambia at London School of Hygiene and Tropical Medicine, Fajara, Gambia
• ²Division of Experimental Medicine, University of California, San Francisco, San Francisco, California, United States
• ³Statistics and Bioinformatics, Medical Research Council Unit The Gambia at London School of Hygiene and Tropical Medicine, Fajara, Gambia
• ⁴Ludwig Maximilian University of Munich, Munich, Bavaria, Germany
• ⁵Aurum Institute, Johannesburg, South Africa
• ⁶German Center for Infection Research (DZIF), Partner site Munich, Braunschweig, Bavaria, Germany
• ⁷Department of Infectious Diseases and Tropical Medicine, LMU Munich University Hospital, Munich, Bavaria, Germany
• ⁸Unit Global Health, Helmholtz Zentrum München, German Research Centre for Environmental Health (HMGU), Neuherberg, Germany
• ⁹Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology, Infection and Pandemic Research, Türkenstraße 87, 80799, Munich, Germany
• ¹⁰Department of Infection Biology, London School of Hygiene and Tropical Medicine, University of London, London, London, United Kingdom
• ¹¹Vaccine and Immunity theme, Medical Research Council The Gambia Unit (MRC), Banjul, Gambia

Background: Despite availability of effective treatment regimens for drug-susceptible TB, some patients still experience poor treatment outcomes. Currently tools for monitoring treatment outcomes are dependent on detection of mycobacteria in sputum, which are slow, expensive and poor at predicting relapse and failure. This study aims to identify new blood-derived markers for predicting treatment response and outcomes. Methods: Whole blood was collected in PAXgene tubes from patients with microbiologically confirmed TB at diagnosis, week 2, and at months 2, 4 and 6. Treatment response and outcomes were determined by culture and gene expression was compared between slow and fast responders; and between patients with good (cured) and poor treatment outcomes (failure and recurrent TB) using targeted RNA gene expression. Gene signatures were developed using random forest classification models.Results: Significant changes in gene expression were detected over the course of the TB treatment. Notably, major gene expression differences were observed at diagnosis between subsequently cured patients and patients who experienced poor treatment outcomes while minimal changes were detected between slow and fast responders among cured patients at diagnosis. A 7-gene end of treatment signature distinguished patients with good outcomes from those with poor treatment outcomes with AUCs of 0.91 (95% CI 0.85-0.99), 0.98 (95% CI 0.96-0.99), and 1.0 (95% CI 0.99-1.00), at baseline, month 2 and month 6 respectively. Additionally, a 6-gene month 2 signature discriminates slow from fast responders with AUCs of 0.49 (95% CI 0.33-0.64), 0.58 (95% CI 0.07-1.00), and 0.93 (95% CI 0.78-1.00) at diagnosis, week 2 and month 2 respectively.The study identified genes signatures associated with TB treatment response and outcomes suggesting potential utility for treatment monitoring.