title: An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis.
abstract: 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.
authors: Division of Immunoregulation, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
authors: Matthew P R
authors: MP
authors: Berry
authors: Christine M
authors: CM
authors: Graham
authors: Finlay W
authors: FW
authors: McNab
authors: Zhaohui
authors: Z
authors: Xu
authors: Susannah A A
authors: SA
authors: Bloch
authors: Tolu
authors: T
authors: Oni
authors: Katalin A
authors: KA
authors: Wilkinson
authors: Romain
authors: R
authors: Banchereau
authors: Jason
authors: J
authors: Skinner
authors: Robert J
authors: RJ
authors: Wilkinson
authors: Charles
authors: C
authors: Quinn
authors: Derek
authors: D
authors: Blankenship
authors: Ranju
authors: R
authors: Dhawan
authors: John J
authors: JJ
authors: Cush
authors: Asuncion
authors: A
authors: Mejias
authors: Octavio
authors: O
authors: Ramilo
authors: Onn M
authors: OM
authors: Kon
authors: Virginia
authors: V
authors: Pascual
authors: Jacques
authors: J
authors: Banchereau
authors: Damien
authors: D
authors: Chaussabel
authors: Anne
authors: A
authors: O'Garra
mesh_terms: D001769:Blood / Q000378:metabolism; D016022:Case-Control Studies; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D007370:Interferon Type I / Q000276:immunology*; D055985:Latent Tuberculosis / Q000097:blood / Q000175:diagnosis / Q000235:genetics / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000235:genetics; D009169:Mycobacterium tuberculosis / Q000276:immunology; D009504:Neutrophils / Q000276:immunology*; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000235:genetics*; D014376:Tuberculosis / Q000097:blood* / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology; D014397:Tuberculosis, Pulmonary / Q000097:blood / Q000175:diagnosis / Q000235:genetics / Q000276:immunology
chemical_list: D007370:Interferon Type I