Distinct Phases of Blood Gene Expression Pattern Through Tuberculosis Treatment Reflect Modulation of the Humoral Immune Response

• Published in: The Journal of infectious diseases Vol. 207; no. 1; pp. 18 - 29
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.01.2013
• Subjects: Adolescent; Adult; Aged; Antitubercular Agents - therapeutic use; B-Lymphocytes - drug effects; BACTERIA; Biological and medical sciences; Cohort Studies; Complement C1q - drug effects; Complement C2 - drug effects; Down-Regulation - drug effects; Drug Therapy, Combination; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling; Gene Expression Regulation - drug effects; Humans; Immunity, Humoral - drug effects; Infectious diseases; Isoniazid - therapeutic use; Male; Medical sciences; Microbiology; Middle Aged; Mycobacterium; Mycobacterium tuberculosis - drug effects; Oligonucleotide Array Sequence Analysis; Prospective Studies; Rifampin - therapeutic use; Tuberculosis, Pulmonary - drug therapy; Tuberculosis, Pulmonary - immunology; Tuberculosis, Pulmonary - microbiology; Up-Regulation - drug effects; Young Adult; Infection; Immune response; Treatment; Gene expression; Humoral immunity; Blood
• ISSN: 0022-1899; 1537-6613; 1537-6613
• DOI: 10.1093/infdis/jis499

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, largescale 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.