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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 treatment1,2. 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 disease3. The immune response to M. tuberculosis is complex and incompletely characterized, hindering development of new diagnostics, therapies and vaccines4,5. 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.

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Figure 1: A distinct whole-blood 393-gene transcriptional signature of active TB.
Figure 2: A distinct whole-blood 86-gene transcriptional signature of active TB is distinct from other diseases.
Figure 3: Whole-blood transcriptional signature of active TB reflects distinct changes in cellular composition and gene expression.
Figure 4: Interferon-inducible gene expression in active TB.

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Primary accessions

Gene Expression Omnibus

Data deposits

All microarray data are deposited in GEO under accession numbers GSE19491, GSE19444, GSE19443, GSE19442, GSE19439, GSE19435 and GSE 22098. Some of the work has been submitted as US patent application PCT 371: Blood Transcriptional Signature of Mycobacterium Tuberculosis Infection: Serial No: 12/602,488.

References

  1. Dye, C., Floyd, K. & Uplekar, M. in Global Tuberculosis Control: Surveillance, Planning, Financing Ch. 1, 17–37 (World Health Organization, 2008)

    Google Scholar 

  2. Kaufmann, S. H. & McMichael, A. J. Annulling a dangerous liaison: vaccination strategies against AIDS and tuberculosis. Nature Med. 11, S33–S44 (2005)

    Article  CAS  Google Scholar 

  3. Barry, C. E., III et al. The spectrum of latent tuberculosis: rethinking the biology and intervention strategies. Nature Rev. Microbiol. 7, 845–855 (2009)

    Article  CAS  Google Scholar 

  4. Cooper, A. M. Cell-mediated immune responses in tuberculosis. Annu. Rev. Immunol. 27, 393–422 (2009)

    Article  CAS  Google Scholar 

  5. Young, D. B., Perkins, M. D., Duncan, K. & Barry, C. E., III Confronting the scientific obstacles to global control of tuberculosis. J. Clin. Invest. 118, 1255–1265 (2008)

    Article  CAS  Google Scholar 

  6. Ardura, M. I. et al. Enhanced monocyte response and decreased central memory T cells in children with invasive Staphylococcus aureus infections. PLoS ONE 4, e5446 (2009)

    Article  ADS  Google Scholar 

  7. Chaussabel, D. et al. A modular analysis framework for blood genomics studies: application to systemic lupus erythematosus. Immunity 29, 150–164 (2008)

    Article  CAS  Google Scholar 

  8. Pascual, V., Chaussabel, D. & Banchereau, J. A genomic approach to human autoimmune diseases. Annu. Rev. Immunol. 28, 535–571 (2010)

    Article  CAS  Google Scholar 

  9. Ramilo, O. et al. Gene expression patterns in blood leukocytes discriminate patients with acute infections. Blood 109, 2066–2077 (2007)

    Article  CAS  Google Scholar 

  10. Falk, A. & O’Connor, J. B. in Diagnosis Standards and Classification of Tuberculosis, vol. 12 (eds Falk, A. et al.), 68–76 (National Tuberculosis and Respiratory Disease Association, 1969)

    Google Scholar 

  11. Pankla, R. et al. Genomic transcriptional profiling identifies a candidate blood biomarker signature for the diagnosis of septicemic melioidosis. Genome Biol. 10, R127.1–R127.22 (2009)

    Article  Google Scholar 

  12. Allantaz, F. et al. Blood leukocyte microarrays to diagnose systemic onset juvenile idiopathic arthritis and follow the response to IL-1 blockade. J. Exp. Med. 204, 2131–2144 (2007)

    Article  CAS  Google Scholar 

  13. Baechler, E. C. et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc. Natl Acad. Sci. USA 100, 2610–2615 (2003)

    Article  CAS  ADS  Google Scholar 

  14. Bennett, L. et al. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J. Exp. Med. 197, 711–723 (2003)

    Article  CAS  Google Scholar 

  15. Beck, J. S., Potts, R. C., Kardjito, T. & Grange, J. M. T4 lymphopenia in patients with active pulmonary tuberculosis. Clin. Exp. Immunol. 60, 49–54 (1985)

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Auffray, C., Sieweke, M. H. & Geissmann, F. Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu. Rev. Immunol. 27, 669–692 (2009)

    Article  CAS  Google Scholar 

  17. Casanova, J. L. & Abel, L. Genetic dissection of immunity to mycobacteria: the human model. Annu. Rev. Immunol. 20, 581–620 (2002)

    Article  CAS  Google Scholar 

  18. Flynn, J. L. & Chan, J. Immunology of tuberculosis. Annu. Rev. Immunol. 19, 93–129 (2001)

    Article  CAS  Google Scholar 

  19. Decker, T., Muller, M. & Stockinger, S. The yin and yang of type I interferon activity in bacterial infection. Nature Rev. Immunol. 5, 675–687 (2005)

    Article  CAS  Google Scholar 

  20. Manca, C. et al. Hypervirulent M. tuberculosis W/Beijing strains upregulate type I IFNs and increase expression of negative regulators of the Jak-Stat pathway. J. Interferon Cytokine Res. 25, 694–701 (2005)

    Article  CAS  ADS  Google Scholar 

  21. Ordway, D. et al. The hypervirulent Mycobacterium tuberculosis strain HN878 induces a potent TH1 response followed by rapid down-regulation. J. Immunol. 179, 522–531 (2007)

    Article  CAS  Google Scholar 

  22. Manca, C. et al. Virulence of a Mycobacterium tuberculosis clinical isolate in mice is determined by failure to induce Th1 type immunity and is associated with induction of IFN-alpha/beta. Proc. Natl Acad. Sci. USA 98, 5752–5757 (2001)

    Article  CAS  ADS  Google Scholar 

  23. Cooper, A. M., Pearl, J. E., Brooks, J. V., Ehlers, S. & Orme, I. M. Expression of the nitric oxide synthase 2 gene is not essential for early control of Mycobacterium tuberculosis in the murine lung. Infect. Immun. 68, 6879–6882 (2000)

    Article  CAS  Google Scholar 

  24. Telesca, C. et al. Interferon-alpha treatment of hepatitis D induces tuberculosis exacerbation in an immigrant. J. Infect. 54, e223–e226 (2007)

    Article  Google Scholar 

  25. Eum, S. Y. et al. Neutrophils are the predominant infected phagocytic cells in the airways of patients with active pulmonary tuberculosis. Chest 137, 122–128 (2010)

    Article  Google Scholar 

  26. Eruslanov, E. B. et al. Neutrophil responses to Mycobacterium tuberculosis infection in genetically susceptible and resistant mice. Infect. Immun. 73, 1744–1753 (2005)

    Article  CAS  Google Scholar 

  27. Jacobsen, M. et al. Candidate biomarkers for discrimination between infection and disease caused by Mycobacterium tuberculosis. J. Mol. Med. 85, 613–621 (2007)

    Article  CAS  Google Scholar 

  28. Mistry, R. et al. Gene-expression patterns in whole blood identify subjects at risk for recurrent tuberculosis. J. Infect. Dis. 195, 357–365 (2007)

    Article  CAS  Google Scholar 

  29. Salisbury, D., Ramsay, M. & Noakes, K. in Immunization against Infectious Disease 3rd edn 391–408 (HMSO, 2006)

    Google Scholar 

  30. National Institute for Health and Clinical Excellence. Tuberculosis. Clinical Diagnosis and Management of Tuberculosis, and Measures for its Prevention and Control (Royal College of Physicians, 2006)

Download references

Acknowledgements

We thank the patients and volunteer participants. We thank D. Kioussis (MRC National Institute for Medical Research (NIMR)) and D. Young (NIMR) for discussion and input. We thank N. Baldwin (Baylor Institute for Immunology Research (BIIR)) for advice and support on bioinformatics analysis, Q.-A. Nguyen (BIIR) and colleagues for providing technical assistance with microarray processing, and S. Caidan (NIMR), J. Wills (NIMR) and S. Phillips (BIIR) for help and advice with sample storage and transport. We thank the TB service at Imperial College Healthcare NHS Trust, B.M. Haselden and the TB service at Hillingdon Hospital, Uxbridge, UK. We also thank H. Giedon and R. Seldon for help in laboratory analyses, and Y. Hlombe for recruitment of patients and follow-up in South Africa. A. Rae (NIMR), T. Dipucchio (BIIR) and K. Palucka (BIIR) provided advice on flow cytometry. We thank G. Hayward for help depositing the microarray data. We thank J. Brock (NIMR) for help with graphics. M.P.R.B. was supported by an MRC career development fellowship and a grant from the Dana Foundation Program in Human Immunology. The research was funded by the Medical Research Council, UK, MRC Grant U117565642 and The Dana Foundation Program in Human Immunology. A.O’G., C.M.G. and F.W.McN. are funded by the Medical Research Council, UK. V.P. is supported by National Institutes of Health (NIH) R01 AR050770-01, NIH P50 ARO54083 and NIH 1 U19 AI082715-01. The work of J.B., D.C. and V.P. is supported by the Baylor Health Care System Foundation and the NIH (U19 AIO57234-02, U01 AI082110, P01 CA084512).

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Authors

Contributions

M.P.R.B., D.C., O.M.K and A.O’G. designed the study on TB with input from J.B. and R.J.W. and for other diseases with input from V.P. and O.R.; M.P.R.B., S.A.A.B., T.O., K.A.W., J.J.C., A.M., R.B. and O.M.K. recruited, sampled and collected data about patients; M.P.R.B., R.B., A.M. and C.M.G. processed whole blood for microarray experiments with help from J.S.; C.G. performed blood-cell subset separations and processing for microarray experiments with help from J.S.; M.P.R.B., C.M.G. and Z.X. performed microarray data analysis, with advice and input from J.S., D.C. and V.P.; M.P.R.B. and Z.X. performed Ingenuity, modular and ‘molecular distance to health’ analyses; M.P.R.B. performed multiplex serum analyses; F.W.McN. performed flow cytometry analysis; D.C., V.P. and A.O’G. supervised data analysis; M.P.R.B. and D.B. performed statistical analysis; M.P.R.B., S.A.A.B., R.D. and O.M.K performed analyses of radiology; A.O’G. and M.P.R.B. wrote the manuscript, with early input from C.M.G., F.W.McN., J.B., D.C. and J.S., and subsequently all authors provided advice and approved the final manuscript.

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Correspondence to Anne O’Garra.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-11 with legends and Supplementary Tables 1.2 .4 and 7 (see separate files for Supplementary Tables 3, 5 and 6). (PDF 27535 kb)

Supplementary Table 3

This table contains 393-transcript list. (XLS 85 kb)

Supplementary Table 5

This table contains patient details. (XLS 25 kb)

Supplementary Table 6

This table contains 86-transcript list. (XLS 31 kb)

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Berry, M., Graham, C., McNab, F. et al. An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis. Nature 466, 973–977 (2010). https://doi.org/10.1038/nature09247

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