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

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posted on 2023-06-09, 00:52 authored by Isobella Honeyborne, Timothy D McHugh, Iitu Kuittinen, Anna Cichonska, Dimitrios Evangelopoulos, Katharina Ronacher, Paul D van Helden, Stephen H Gillespie, Delmiro Fernandez-Reyes, Gerhard Walzl, Juho Rousu, Philip D Butcher, Simon WaddellSimon Waddell
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.

History

Publication status

  • Published

File Version

  • Published version

Journal

BMC Medicine

ISSN

1741-7015

Publisher

BioMed Central

Issue

1

Volume

14

Article number

a68

Department affiliated with

  • BSMS Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2016-04-12

First Open Access (FOA) Date

2016-04-12

First Compliant Deposit (FCD) Date

2016-04-12

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