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


Cliff, JM; Lee, JS; Constantinou, N; Cho, JE; Clark, TG; Ronacher, K; King, EC; Lukey, PT; Duncan, K; Van Helden, PD; Walzl, G; Dockrell, HM; (2012) Distinct phases of blood gene expression pattern through tuberculosis treatment reflect modulation of the humoral immune response. The Journal of infectious diseases, 207 (1). pp. 18-29. ISSN 0022-1899 DOI: 10.1093/infdis/jis499

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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.<br/>

Item Type: Article
Faculty and Department: Academic Services & Administration > Academic Administration
Faculty of Infectious and Tropical Diseases > Dept of Immunology and Infection
Faculty of Epidemiology and Population Health > Dept of Infectious Disease Epidemiology
Faculty of Infectious and Tropical Diseases > Dept of Pathogen Molecular Biology
Research Centre: TB Centre
PubMed ID: 22872737
Web of Science ID: 312604200005
URI: http://researchonline.lshtm.ac.uk/id/eprint/146738

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