Profiling persistent tubercule bacilli from patient sputa during therapy predicts early drug efficacy

Simple item page
dc.contributor.authorHoneyborne, Isobellaen_ZA
dc.contributor.authorMcHugh, Timothy D.en_ZA
dc.contributor.authorKuittinen, Iituen_ZA
dc.contributor.authorCichonska, Annaen_ZA
dc.contributor.authorEvangelopoulos, Dimitriosen_ZA
dc.contributor.authorRonacher, Katharinaen_ZA
dc.contributor.authorVan Helden, Paul D.en_ZA
dc.contributor.authorGillespie, Stephen H.en_ZA
dc.contributor.authorFernandez-Reyes, Delmiroen_ZA
dc.contributor.authorWalzl, Gerharden_ZA
dc.contributor.authorRousu, Juhoen_ZA
dc.contributor.authorButcher, Philip D.en_ZA
dc.contributor.authorWaddell, Simon J.en_ZA
dc.date.accessioned2017-01-24T10:38:07Z
dc.date.available2017-01-24T10:38:07Z
dc.date.issued2016-04-07
dc.date.updated2016-12-09T12:08:18Z
dc.descriptionCITATION: Honeyborne, I., et al. 2016. Profiling persistent tubercule bacilli from patient sputa during therapy predicts early drug efficacy. BMC Medicine, 14:68, doi:10.1186/s12916-016-0609-3.
dc.descriptionThe original publication is available at https://bmcmedicine.biomedcentral.com
dc.description.abstractBackground: 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.en_ZA
dc.description.urihttps://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-016-0609-3
dc.description.versionPublisher's versionen_ZA
dc.format.extent13 pages : illustrations (some colour)en_ZA
dc.identifier.citationHoneyborne, I., et al. 2016. Profiling persistent tubercule bacilli from patient sputa during therapy predicts early drug efficacy. BMC Medicine, 14:68, doi:10.1186/s12916-016-0609-3en_ZA
dc.identifier.issn1741-7015 (Online)
dc.identifier.otherdoi:10.1186/s12916-016-0609-3
dc.identifier.urihttp://hdl.handle.net/10019.1/100509
dc.language.isoen_ZAen_ZA
dc.publisherBioMed Centralen_ZA
dc.rights.holderAuthor retains copyrighten_ZA
dc.subjectMycobacterium tuberculosisen_ZA
dc.subjectTuberculosis -- Patientsen_ZA
dc.subjectAntitubercular agentsen_ZA
dc.subjectSputum -- Microbiologyen_ZA
dc.titleProfiling persistent tubercule bacilli from patient sputa during therapy predicts early drug efficacyen_ZA
dc.typeArticleen_ZA
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
honeyborne_profiling_2016.pdf
Size:
2.94 MB
Format:
Adobe Portable Document Format
Description:
Download article
Download
License bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
license.txt
Size:
1.95 KB
Format:
Item-specific license agreed upon to submission
Description:
Download
Collections
Research Articles (Molecular Biology and Human Genetics)