An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis

Matthew P R Berry, Christine M. Graham, Finlay W. McNab, Zhaohui Xu, Susannah A A Bloch, Tolu Oni, Katalin A. Wilkinson, Romain Banchereau, Jason Skinner, Robert J. Wilkinson, Charles Quinn, Derek Blankenship, Ranju Dhawan, John J. Cush, Asuncion Mejias, Octavio Ramilo, Onn M. Kon, Virginia Pascual, Jacques Banchereau, Damien J. ChaussabelAnne O'Garra

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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-γ and type I IFN-αβ 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-αβ 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.

Original languageEnglish
Pages (from-to)973-977
Number of pages5
JournalNature
Volume466
Issue number7309
DOIs
Publication statusPublished - 19 Aug 2010
Externally publishedYes

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ASJC Scopus subject areas

  • General
  • Medicine(all)

Cite this

Berry, M. P. R., Graham, C. M., McNab, F. W., Xu, Z., Bloch, S. A. A., Oni, T., Wilkinson, K. A., Banchereau, R., Skinner, J., Wilkinson, R. J., Quinn, C., Blankenship, D., Dhawan, R., Cush, J. J., Mejias, A., Ramilo, O., Kon, O. M., Pascual, V., Banchereau, J., ... O'Garra, A. (2010). An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis. Nature, 466(7309), 973-977. https://doi.org/10.1038/nature09247