Eckold, Clare; van Doorn, Cassandra LR; Ruslami, Rovina; Ronacher, Katharina; Riza, Anca-Lelia; van Veen, Suzanne; Lee, Ji-Sook; Kumar, Vinod; Kerry-Barnard, Sarah; Malherbe, Stephanus T; +16 more... Kleynhans, Léanie; Stanley, Kim; Joosten, Simone A; Critchley, Julia A; Hill, Philip C; van Crevel, Reinout; Wijmenga, Cisca; Haks, Mariëlle C; Ioana, Mihai; Alisjahbana, Bachti; Walzl, Gerhard; Ottenhoff, Tom HM; Dockrell, Hazel M; Vianello, Eleonora; Cliff, Jacqueline M; TANDEM Consortium$; (2023) Impaired resolution of blood transcriptomes through tuberculosis treatment with diabetes comorbidity. Clinical and translational medicine, 13 (9). e1375-. ISSN 2001-1326 DOI: https://doi.org/10.1002/ctm2.1375
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Abstract
BACKGROUND: 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 diagnosis. It is unknown whether this persists through treatment and contributes to the adverse outcomes. METHODS: Pulmonary TB patients recruited in South Africa, Indonesia and Romania were classified as having TB-DM, TB with prediabetes, TB-related hyperglycaemia or TB-only, based on glycated haemoglobin concentration at TB diagnosis and after 6 months of TB treatment. Gene expression in blood at diagnosis and intervals throughout treatment was measured by unbiased RNA-Seq and targeted Multiplex Ligation-dependent Probe Amplification. Transcriptomic data were analysed by longitudinal mixed-model regression to identify whether genes were differentially expressed between clinical groups through time. Predictive models of TB-treatment response across groups were developed and cross-tested. RESULTS: Gene expression differed between TB and TB-DM patients at diagnosis and was modulated by TB treatment in all clinical groups but to different extents, such that differences remained in TB-DM relative to TB-only throughout. Expression of some genes increased through TB treatment, whereas others decreased: some were persistently more highly expressed in TB-DM and others in TB-only patients. Genes involved in innate immune responses, anti-microbial immunity and inflammation were significantly upregulated in people with TB-DM throughout treatment. The overall pattern of change was similar across clinical groups irrespective of diabetes status, permitting models predictive of TB treatment to be developed. CONCLUSIONS: Exacerbated transcriptome changes in TB-DM take longer to resolve during TB treatment, meaning they remain different from those in uncomplicated TB after treatment completion. This may indicate a prolonged inflammatory response in TB-DM, requiring prolonged treatment or host-directed therapy for complete cure. Development of transcriptome-based biomarker signatures of TB-treatment response should include people with diabetes for use across populations.
Item Type | Article |
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Faculty and Department | Faculty of Infectious and Tropical Diseases > Department of Infection Biology |
Research Centre | TB Centre |
PubMed ID | 37649224 |
Elements ID | 208377 |
Official URL | http://dx.doi.org/10.1002/ctm2.1375 |
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Filename: Eckold-etal-2022-Impaired-resolution-of-blood-transcriptomes-through-tuberculosis-treatment-with-diabetes-comorbidity.pdf
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