Distinct phases of blood gene expression pattern through tuberculosis treatment reflect modulation of the humoral immune response

Cliff, Jacqueline M., Lee, Ji-Sook, Constantinou, Nicholas, Cho, Jang-Eun, Clark, Taane G., Ronacher, Katharina, King, Elizabeth C., Lukey, Pauline T., Duncan, Ken, Van Helden, Paul D., Walzl, Gerhard and Dockrell, Hazel M. (2013) Distinct phases of blood gene expression pattern through tuberculosis treatment reflect modulation of the humoral immune response. Journal of Infectious Diseases, 207 1: 18-29. doi:10.1093/infdis/jis499


Author Cliff, Jacqueline M.
Lee, Ji-Sook
Constantinou, Nicholas
Cho, Jang-Eun
Clark, Taane G.
Ronacher, Katharina
King, Elizabeth C.
Lukey, Pauline T.
Duncan, Ken
Van Helden, Paul D.
Walzl, Gerhard
Dockrell, Hazel M.
Title Distinct phases of blood gene expression pattern through tuberculosis treatment reflect modulation of the humoral immune response
Journal name Journal of Infectious Diseases   Check publisher's open access policy
ISSN 0022-1899
1537-6613
Publication date 2013-01-01
Year available 2013
Sub-type Article (original research)
DOI 10.1093/infdis/jis499
Open Access Status Not yet assessed
Volume 207
Issue 1
Start page 18
End page 29
Total pages 12
Place of publication Cary, NC United States
Publisher Oxford University Press
Language eng
Formatted abstract
Background. Accurate assessment of treatment efficacy would facilitate clinical trials of new antituberculosis drugs. We hypothesized that early alterations in peripheral immunity could be measured by gene expression profiling in tuberculosis patients undergoing successful conventional combination treatment.

Methods. Ex vivo blood samples from 27 pulmonary tuberculosis patients were assayed at diagnosis and during treatment. RNA was processed and hybridized to Affymetrix GeneChips, to determine expression of over 47 000 transcripts.

Results. There were significant ≥2-fold changes in expression of >4000 genes during treatment. Rapid, large-scale changes were detected, with down-regulated expression of 1261 genes within the first week, including inflammatory markers such as complement components C1q and C2. This was followed by slower changes in expression of different networks of genes, including a later increase in expression of B-cell markers, transcription factors, and signaling molecules.

Conclusions. The fast initial down-regulation of expression of inflammatory mediators coincided with rapid killing of actively dividing bacilli, whereas slower delayed changes occurred as drugs acted on dormant bacilli and coincided with lung pathology resolution. Measurement of biosignatures during clinical trials of new drugs could be useful predictors of rapid bactericidal or sterilizing drug activity, and would expedite the licensing of new treatment regimens.
Keyword Tuberculosis
Transcriptomics
Biomarker
Drug treatment
Complement
B-cell
Clinical trial
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 48941
IP. 09.32040.011
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Mater Research Institute-UQ (MRI-UQ)
 
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Created: Thu, 16 Feb 2017, 11:33:53 EST by Johanna Barclay on behalf of Mater Research Institute-UQ