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

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dc.contributorAalto-yliopistofi
dc.contributorAalto Universityen
dc.contributor.authorHoneyborne, Isobellaen_US
dc.contributor.authorMcHugh, Timothy D.en_US
dc.contributor.authorKuittinen, Iituen_US
dc.contributor.authorCichonska, Annaen_US
dc.contributor.authorEvangelopoulos, Dimitriosen_US
dc.contributor.authorRonacher, Katharinaen_US
dc.contributor.authorvan Helden, Paul D.en_US
dc.contributor.authorGillespie, Stephen H.en_US
dc.contributor.authorFernandez-Reyes, Delmiroen_US
dc.contributor.authorWalzl, Gerharden_US
dc.contributor.authorRousu, Juhoen_US
dc.contributor.authorButcher, Philip D.en_US
dc.contributor.authorWaddell, Simon J.en_US
dc.contributor.departmentDepartment of Computer Scienceen
dc.contributor.groupauthorProfessorship Rousu Juhoen
dc.contributor.organizationUniversity College Londonen_US
dc.contributor.organizationStellenbosch Universityen_US
dc.contributor.organizationUniversity of St Andrewsen_US
dc.contributor.organizationSt. George's University of Londonen_US
dc.contributor.organizationUniversity of Sussexen_US
dc.date.accessioned2017-05-11T09:06:55Z
dc.date.available2017-05-11T09:06:55Z
dc.date.issued2016-04-07en_US
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
dc.description.versionPeer revieweden
dc.format.extent1-13
dc.format.mimetypeapplication/pdfen_US
dc.identifier.citationHoneyborne, 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, 68, pp. 1-13 . https://doi.org/10.1186/s12916-016-0609-3en
dc.identifier.doi10.1186/s12916-016-0609-3en_US
dc.identifier.issn1741-7015
dc.identifier.otherPURE UUID: c6246ad1-8035-45c8-9fe8-dffd65aac360en_US
dc.identifier.otherPURE ITEMURL: https://research.aalto.fi/en/publications/c6246ad1-8035-45c8-9fe8-dffd65aac360en_US
dc.identifier.otherPURE LINK: http://www.scopus.com/inward/record.url?scp=84962861468&partnerID=8YFLogxKen_US
dc.identifier.otherPURE FILEURL: https://research.aalto.fi/files/11443855/art_10.1186_s12916_016_0609_3.pdfen_US
dc.identifier.urihttps://aaltodoc.aalto.fi/handle/123456789/25844
dc.identifier.urnURN:NBN:fi:aalto-201705114219
dc.language.isoenen
dc.relation.ispartofseriesBMC MEDICINEen
dc.relation.ispartofseriesVolume 14, issue 1en
dc.rightsopenAccessen
dc.subject.keywordMycobacterium tuberculosisen_US
dc.subject.keywordPersistent infectionen_US
dc.subject.keywordPredictive biomarkeren_US
dc.subject.keywordSputumen_US
dc.subject.keywordTranscriptional profilingen_US
dc.titleProfiling persistent tubercule bacilli from patient sputa during therapy predicts early drug efficacyen
dc.typeA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessäfi
dc.type.versionpublishedVersion
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