Gene expression signatures identify biologically and clinically distinct tuberculosis endotypes
| Autor: | DiNardo, A., Gandhi, T., Heyckendorf, J., Grimm, S., Rajapakshe, K., Nishiguchi, T., Reimann, M., Kirchner, H., Kahari, J., Dlamini, Q., Lange, C., Goldmann, T., Marwitz, S., group, D., Abhimanyu, Cirillo, J., Kaufmann, S., Netea, M., van Crevel, R., Mandalakas, A., Coarfa, C. |
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| Přispěvatelé: | VU University medical center, DZIF-TB cohort study group |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Pulmonary and Respiratory Medicine
Inflammation Endotype Tuberculosis biology business.industry lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] NFAT medicine.disease biology.organism_classification Mycobacterium tuberculosis Immune system lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4] Immunity Immunopathology Immunology medicine Cytokines Humans RNA Hormone metabolism business Transcriptome |
| Zdroj: | Eur Respir J European Respiratory Journal, 60 European Respiratory Journal, 60(3):2102263. European Respiratory Society European Respiratory Journal, 60, 3 DZIF-TB cohort study group 2022, ' Gene expression signatures identify biologically and clinically distinct tuberculosis endotypes ', European Respiratory Journal, vol. 60, no. 3, 2102263 . https://doi.org/10.1183/13993003.02263-2021 European Respiratory Journal |
| ISSN: | 0903-1936 |
| Popis: | BackgroundIn vitro, animal model, and clinical evidence suggests that tuberculosis is not a monomorphic disease, and that host response to tuberculosis is protean with multiple distinct molecular pathways and pathologies (endotypes). We applied unbiased clustering to identify separate tuberculosis endotypes with classifiable gene expression patterns and clinical outcomes.MethodsA cohort comprised of microarray gene expression data from microbiologically confirmed tuberculosis patients were used to identify putative endotypes. One microarray cohort with longitudinal clinical outcomes was reserved for validation, as was one RNA-seq cohorts. Finally, a separate cohort of tuberculosis patients with functional immune results was evaluated to clarify stimulated from unstimulated immune responses.ResultsA discovery cohort, including 435 tuberculosis patients and 533 asymptomatic controls, identified two tuberculosis endotypes. Tuberculosis patient endotype A is characterized by increased expression of genes related to inflammation and immunity and decreased metabolism and proliferation; in contrast, endotype B increased activity of metabolism and proliferation pathways. An independent RNA-seq validation cohort, including 118 tuberculosis patients and 179 controls, validated the discovery results. Gene expression signatures for treatment failure were elevated in endotype A in the discovery cohort, and a separate validation cohort confirmed that endotype A patients had slower time to culture conversion, and a reduced incidence of cure. These observations suggest that endotypes reflect functional immunity, supported by the observation that tuberculosis patients with a hyperinflammatory endotype have less responsive cytokine production upon stimulation.ConclusionThese findings provide evidence that metabolic and immune profiling could inform optimization of endotype-specific host-directed therapies for tuberculosis. |
| Databáze: | OpenAIRE |
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