Distinct Phases of Blood Gene Expression Pattern Through Tuberculosis Treatment Reflect Modulation of the Humoral Immune Response
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 t...
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| Published in | The Journal of infectious diseases Vol. 207; no. 1; pp. 18 - 29 |
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| Main Authors | , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Oxford
Oxford University Press
01.01.2013
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| Subjects | |
| Online Access | Get full text |
| ISSN | 0022-1899 1537-6613 1537-6613 |
| 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, 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. |
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| AbstractList | 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.
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.
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.
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. 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. 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 > or =,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. 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.BACKGROUNDAccurate 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.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.METHODSEx 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.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.RESULTSThere 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.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.CONCLUSIONSThe 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. |
| Author | Ronacher, Katharina King, Elizabeth C. Lee, Ji-Sook Duncan, Ken Walzl, Gerhard Cliff, Jacqueline M. Clark, Taane G. Dockrell, Hazel M. Van Helden, Paul D. Cho, Jang-Eun Lukey, Pauline T. Constantinou, Nicholas |
| Author_xml | – sequence: 1 givenname: Jacqueline M. surname: Cliff fullname: Cliff, Jacqueline M. – sequence: 2 givenname: Ji-Sook surname: Lee fullname: Lee, Ji-Sook – sequence: 3 givenname: Nicholas surname: Constantinou fullname: Constantinou, Nicholas – sequence: 4 givenname: Jang-Eun surname: Cho fullname: Cho, Jang-Eun – sequence: 5 givenname: Taane G. surname: Clark fullname: Clark, Taane G. – sequence: 6 givenname: Katharina surname: Ronacher fullname: Ronacher, Katharina – sequence: 7 givenname: Elizabeth C. surname: King fullname: King, Elizabeth C. – sequence: 8 givenname: Pauline T. surname: Lukey fullname: Lukey, Pauline T. – sequence: 9 givenname: Ken surname: Duncan fullname: Duncan, Ken – sequence: 10 givenname: Paul D. surname: Van Helden fullname: Van Helden, Paul D. – sequence: 11 givenname: Gerhard surname: Walzl fullname: Walzl, Gerhard – sequence: 12 givenname: Hazel M. surname: Dockrell fullname: Dockrell, Hazel M. |
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| SubjectTerms | 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 |
| Title | Distinct Phases of Blood Gene Expression Pattern Through Tuberculosis Treatment Reflect Modulation of the Humoral Immune Response |
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