Detectable changes in the blood transcriptome are present after two weeks of antituberculosis therapy.
BACKGROUND
Globally there are approximately 9 million new active tuberculosis cases and 1.4 million deaths annually. Effective antituberculosis treatment monitoring is difficult as there are no existing biomarkers of poor adherence or inadequate treatment earlier than 2 months after treatment initiation. Inadequate treatment leads to worsening disease, disease transmission and drug resistance.


OBJECTIVE
To determine if blood transcriptional signatures change in response to antituberculosis treatment and could act as early biomarkers of a successful response.


METHODS
Blood transcriptional profiles of untreated active tuberculosis patients in South Africa were analysed before, during (2 weeks and 2 months), at the end of (6 months) and after (12 months) antituberculosis treatment, and compared to individuals with latent tuberculosis. An active-tuberculosis transcriptional signature and a specific treatment-response transcriptional signature were derived. The specific treatment response transcriptional signature was tested in two independent cohorts. Two quantitative scoring algorithms were applied to measure the changes in the transcriptional response. The most significantly represented pathways were determined using Ingenuity Pathway Analysis.


RESULTS
An active tuberculosis 664-transcript signature and a treatment specific 320-transcript signature significantly diminished after 2 weeks of treatment in all cohorts, and continued to diminish until 6 months. The transcriptional response to treatment could be individually measured in each patient.


CONCLUSIONS
Significant changes in the transcriptional signatures measured by blood tests were readily detectable just 2 weeks after treatment initiation. These findings suggest that blood transcriptional signatures could be used as early surrogate biomarkers of successful treatment response.
Division of Immunoregulation, MRC National Institute for Medical Research, London, United Kingdom. cbloom@nimr.mrc.ac.uk
Chloe I
CI
Bloom
Christine M
CM
Graham
Matthew P R
MP
Berry
Katalin A
KA
Wilkinson
Tolu
T
Oni
Fotini
F
Rozakeas
Zhaohui
Z
Xu
Jose
J
Rossello-Urgell
Damien
D
Chaussabel
Jacques
J
Banchereau
Virginia
V
Pascual
Marc
M
Lipman
Robert J
RJ
Wilkinson
Anne
A
O'Garra
D000293:Adolescent; D000328:Adult; D000368:Aged; D000995:Antitubercular Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D016000:Cluster Analysis; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D020411:Oligonucleotide Array Sequence Analysis; D017063:Outcome Assessment, Health Care / Q000379:methods; D013997:Time Factors; D059467:Transcriptome / Q000187:drug effects* / Q000235:genetics; D014376:Tuberculosis / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D055815:Young Adult
D000995:Antitubercular Agents; D015415:Biomarkers