Profiling persistent tubercule bacilli from patient sputa during therapy predicts early drug efficacy
Date
2016-04-07
Journal Title
Journal ISSN
Volume Title
Publisher
BioMed Central
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.
Description
CITATION: 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.
The original publication is available at https://bmcmedicine.biomedcentral.com
The original publication is available at https://bmcmedicine.biomedcentral.com
Keywords
Mycobacterium tuberculosis, Tuberculosis -- Patients, Antitubercular agents, Sputum -- Microbiology
Citation
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