Profiling persistent tubercule bacilli from patient sputa during therapy predicts early drug efficacy
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Background. New treatment options are needed to maintain and improve therapy for tuberculosis, which caused the death of 1.5 million people in 2013 despite potential for an 86 % treatment success rate. A greater understanding of Mycobacterium tuberculosis (M.tb) bacilli that persist through drug therapy will aid drug development programs. Predictive biomarkers for treatment efficacy are also a research priority. Methods and Results. Genome-wide transcriptional profiling was used to map the mRNA signatures of M.tb from the sputa of 15 patients before and 3, 7 and 14 days after the start of standard regimen drug treatment. The mRNA profiles of bacilli through the first 2 weeks of therapy reflected drug activity at 3 days with transcriptional signatures at days 7 and 14 consistent with reduced M.tb metabolic activity similar to the profile of pre-chemotherapy bacilli. These results suggest that a pre-existing drug-tolerant M.tb population dominates sputum before and after early drug treatment, and that the mRNA signature at day 3 marks the killing of a drug-sensitive sub-population of bacilli. Modelling patient indices of disease severity with bacterial gene expression patterns demonstrated that both microbiological and clinical parameters were reflected in the divergent M.tb responses and provided evidence that factors such as bacterial load and disease pathology influence the host-pathogen interplay and the phenotypic state of bacilli. Transcriptional signatures were also defined that predicted measures of early treatment success (rate of decline in bacterial load over 3 days, TB test positivity at 2 months, and bacterial load at 2 months). Conclusions. This study defines the transcriptional signature of M.tb bacilli that have been expectorated in sputum after two weeks of drug therapy, characterizing the phenotypic state of bacilli that persist through treatment. We demonstrate that variability in clinical manifestations of disease are detectable in bacterial sputa signatures, and that the changing M.tb mRNA profiles 0–2 weeks into chemotherapy predict the efficacy of treatment 6 weeks later. These observations advocate assaying dynamic bacterial phenotypes through drug therapy as biomarkers for treatment success.
Honeyborne , I , McHugh , T D , Kuittinen , I , Cichonska , A , Evangelopoulos , D , Ronacher , K , van Helden , P D , Gillespie , S H , Fernandez-Reyes , D , Walzl , G , Rousu , J , Butcher , P D & Waddell , S J 2016 , ' Profiling persistent tubercule bacilli from patient sputa during therapy predicts early drug efficacy ' BMC Medicine , vol 14 , no. 1 , pp. 1-13 . DOI: 10.1186/s12916-016-0609-3
© 2016 Honeyborne et al. This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
SJW, PDB, SGH and TMcH are part of the PreDiCT-TB consortium (http://www.predict-tb.eu) which is funded from the Innovative Medicines Initiative Joint Undertaking (http://www.imi.europa.eu) under grant agreement No 115337, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution. We would like to thank Kate Gould in the Bacterial Microarray Group at St. George’s for assistance with the microarray work. PDB acknowledges funding from the Wellcome Trust for the Bacterial Microarray Group at St. George’s (grant numbers 062511, 080039, and 086547) for access to M.tb microarrays. IH, TMcH and SGH acknowledge funding from the Medical Research Council (G0601466) and the European Metrology Research Programme (EMRP) INFECT-MET (HLT-08); the EMRP is jointly funded by the EMRP participating countries within EURAMET and the European Union.
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