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

Honeyborne, Isobella, McHugh, Timothy D, Kuittinen, Iitu, Cichonska, Anna, Evangelopoulos, Dimitrios, Ronacher, Katharina, van Helden, Paul D, Gillespie, Stephen H, Fernandez-Reyes, Delmiro, Walzl, Gerhard, Rousu, Juho, Butcher, Philip D and Waddell, Simon J (2016) Profiling persistent tubercule bacilli from patient sputa during therapy predicts early drug efficacy. BMC medicine, 14 (68). ISSN 1741-7015

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Abstract

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.

Item Type: Article
Keywords: Mycobacterium tuberculosis Tuberculosis Infection Transcriptional profiling Microbiology
Schools and Departments: Brighton and Sussex Medical School > Brighton and Sussex Medical School
Brighton and Sussex Medical School > Global Health and Infection
Subjects: Q Science
Q Science > QR Microbiology
Q Science > QR Microbiology > QR0075 Bacteria
Depositing User: Simon Waddell
Date Deposited: 12 Apr 2016 12:17
Last Modified: 05 Aug 2017 18:25
URI: http://sro.sussex.ac.uk/id/eprint/60437

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