GSE193978
Impaired resolution of blood transcriptomes through tuberculosis treatment with diabetes comorbidity
People with diabetes are more likely to develop tuberculosis (TB) and to have poor TB treatment outcomes than those without. We previously showed that blood transcriptomes in people with TB-diabetes (TB-DM) co-morbidity have excessive inflammatory and  reduced interferon responses at TB diagnosis. It is unknown whether this persists through treatment, potentially underlying adverse outcomes.   Methods  Pulmonary TB patients were recruited in South Africa, Indonesia and Romania, and classified as having TB-DM, TB with prediabetes, TB-related hyperglycaemia or uncomplicated TB, based on glycated haemoglobin (HbA1c) concentration at TB diagnosis and after 6 months of TB treatment. Gene expression in blood samples collected at diagnosis and at regular intervals throughout treatment was  measured by unbiased RNA-Seq and targeted Multiplex Ligation-dependent Probe Amplification.   Results   Gene expression was modulated by TB treatment in all groups but to different extents, such that differences remained  in people with TB-DM relative to TB-only throughout, including genes involved in innate responses, anti-microbial immunity and the inflammasome. People with prediabetes or with TB-related hyperglycaemia had gene expression more similar to people with TB-DM than TB-only throughout treatment.  The overall pattern of change was similar across clinical groups irrespective of glycaemic index, permitting models predictive of TB treatment to be developed.  Conclusions  The exacerbated transcriptome changes seen in TB-DM take longer to resolve during TB treatment, indicating that prolonged treatment or host-directed therapy may be needed to improve TB treatment outcomes. Development of transcriptome-based biomarker signatures of TB-treatment response should include people with diabetes to be useful across populations. Overall design: Whole blood was collected from patients with TB-only, TB-DM, TB-IH throughout anti-tuberculosis therapy at four time points: Diagnosis, Week 2, Month 2 and Month 6 in three field sites; South Africa, Romania and Indonesia