Publikationsdatum:
2010-08-21
Beschreibung:
Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis, is a major cause of morbidity and mortality worldwide. Efforts to control it are hampered by difficulties with diagnosis, prevention and treatment. Most people infected with M. tuberculosis remain asymptomatic, termed latent TB, with a 10% lifetime risk of developing active TB disease. Current tests, however, cannot identify which individuals will develop disease. The immune response to M. tuberculosis is complex and incompletely characterized, hindering development of new diagnostics, therapies and vaccines. Here we identify a whole-blood 393 transcript signature for active TB in intermediate and high-burden settings, correlating with radiological extent of disease and reverting to that of healthy controls after treatment. A subset of patients with latent TB had signatures similar to those in patients with active TB. We also identify a specific 86-transcript signature that discriminates active TB from other inflammatory and infectious diseases. Modular and pathway analysis revealed that the TB signature was dominated by a neutrophil-driven interferon (IFN)-inducible gene profile, consisting of both IFN-gamma and type I IFN-alphabeta signalling. Comparison with transcriptional signatures in purified cells and flow cytometric analysis suggest that this TB signature reflects changes in cellular composition and altered gene expression. Although an IFN-inducible signature was also observed in whole blood of patients with systemic lupus erythematosus (SLE), their complete modular signature differed from TB, with increased abundance of plasma cell transcripts. Our studies demonstrate a hitherto underappreciated role of type I IFN-alphabeta signalling in the pathogenesis of TB, which has implications for vaccine and therapeutic development. Our study also provides a broad range of transcriptional biomarkers with potential as diagnostic and prognostic tools to combat the TB epidemic.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3492754/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3492754/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Berry, Matthew P R -- Graham, Christine M -- McNab, Finlay W -- Xu, Zhaohui -- Bloch, Susannah A A -- Oni, Tolu -- Wilkinson, Katalin A -- Banchereau, Romain -- Skinner, Jason -- Wilkinson, Robert J -- Quinn, Charles -- Blankenship, Derek -- Dhawan, Ranju -- Cush, John J -- Mejias, Asuncion -- Ramilo, Octavio -- Kon, Onn M -- Pascual, Virginia -- Banchereau, Jacques -- Chaussabel, Damien -- O'Garra, Anne -- 088316/Wellcome Trust/United Kingdom -- 1 U19 AI082715-01/AI/NIAID NIH HHS/ -- MC_U117565642/Medical Research Council/United Kingdom -- MC_U117588499/Medical Research Council/United Kingdom -- P01 CA084512/CA/NCI NIH HHS/ -- P50 ARO54083/PHS HHS/ -- R01 AR050770-01/AR/NIAMS NIH HHS/ -- U01 AI082110/AI/NIAID NIH HHS/ -- U117565642/Medical Research Council/United Kingdom -- U117588499(88499)/Medical Research Council/United Kingdom -- U19 AI082715/AI/NIAID NIH HHS/ -- U19 AIO57234-02/PHS HHS/ -- England -- Nature. 2010 Aug 19;466(7309):973-7. doi: 10.1038/nature09247.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Immunoregulation, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20725040" target="_blank"〉PubMed〈/a〉
Schlagwort(e):
Blood/metabolism
;
Case-Control Studies
;
*Gene Expression Profiling
;
Gene Expression Regulation/*immunology
;
Humans
;
Interferon Type I/*immunology
;
Latent Tuberculosis/blood/diagnosis/genetics/immunology
;
Lupus Erythematosus, Systemic/blood/genetics
;
Mycobacterium tuberculosis/immunology
;
Neutrophils/*immunology
;
Signal Transduction
;
Transcription, Genetic/*genetics
;
Tuberculosis/*blood/diagnosis/*genetics/immunology
;
Tuberculosis, Pulmonary/blood/diagnosis/genetics/immunology
Print ISSN:
0028-0836
Digitale ISSN:
1476-4687
Thema:
Biologie
,
Chemie und Pharmazie
,
Medizin
,
Allgemeine Naturwissenschaft
,
Physik
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