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E-GEOD-67589 - Excessive Cytolytic Responses Predict Tuberculosis Relapse After Apparently Successful Treatment
Released on 10 September 2015, last updated on 11 September 2015
Background Identification of patients at risk of tuberculosis relapse following treatment would revolutionize clinical trials of new drugs and regimens and facilitate clinical management. The study aim was to determine whether tuberculosis patients who subsequently suffer relapse have different immune responses to mycobacteria in vitro compared to patients who remain cured for two years post-treatment. Methods First episode pulmonary tuberculosis patients were recruited into a surrogate marker study in Cape Town, South Africa. Peripheral blood samples were collected at diagnosis and after two and four weeks of tuberculosis treatment. Diluted blood was cultured with live Mycobacterium tuberculosis for six days and cellular RNA was frozen. Gene expression in samples from ten patients who subsequently relapsed, confirmed by stain genotyping, was compared to those who remained cured using Affymetrix microarrays. Results At diagnosis, the expression of 668 genes was significantly different in samples from patients who subsequently relapsed compared to successfully cured patients, and these differences persisted for at least four weeks. Gene Ontology and biological pathways analyses revealed the most significant difference was up-regulation of genes involved in cytotoxic cell-mediated killing, such as perforin, granulysin and fas ligand. Results were confirmed by qRT-PCR in a wider patient cohort. Conclusions These data show that patients who will subsequently relapse exhibit altered immune responses at diagnosis, including excessively robust cytolytic responses to M. tuberculosis in vitro, compared to patients who will achieve durable cure. Together with microbiological and clinical indices, these differences could be exploited for patient stratification in drugs trials, or for host-directed therapy development. Venous blood samples were diluted in culture medium and stimulated with live M. tuberculosis for 6 days. Samples from 10 TB patients who subsequently relapsed and 10 patients whore remained disease-free for 2 years. Samples collected at TB diagnosis and after 2 weeks or 4 weeks of treatment of first TB episode.
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Jackie Cliff <firstname.lastname@example.org>, Elizabeth C King, Gerhard Walzl, Hazel M Dockrell, Jacqueline M Cliff, Jang-Eun Cho, Ji-Sook Lee, Katharina Ronacher, Paul D Van Helden
Excessive Cytolytic Responses Predict Tuberculosis Relapse After Apparently Successful Treatment. Cliff JM, Cho JE, Lee JS, Ronacher K, King EC, van Helden P, Walzl G, Dockrell HM.