Subjects

Abstract

Tuberculosis remains second only to HIV/AIDS as the leading cause of mortality worldwide due to a single infectious agent1. Despite chemotherapy, the global tuberculosis epidemic has intensified because of HIV co-infection, the lack of an effective vaccine and the emergence of multi-drug-resistant bacteria2,3,4,5. Alternative host-directed strategies could be exploited to improve treatment efficacy and outcome, contain drug-resistant strains and reduce disease severity and mortality6. The innate inflammatory response elicited by Mycobacterium tuberculosis (Mtb) represents a logical host target7. Here we demonstrate that interleukin-1 (IL-1) confers host resistance through the induction of eicosanoids that limit excessive type I interferon (IFN) production and foster bacterial containment. We further show that, in infected mice and patients, reduced IL-1 responses and/or excessive type I IFN induction are linked to an eicosanoid imbalance associated with disease exacerbation. Host-directed immunotherapy with clinically approved drugs that augment prostaglandin E2 levels in these settings prevented acute mortality of Mtb-infected mice. Thus, IL-1 and type I IFNs represent two major counter-regulatory classes of inflammatory cytokines that control the outcome of Mtb infection and are functionally linked via eicosanoids. Our findings establish proof of concept for host-directed treatment strategies that manipulate the host eicosanoid network and represent feasible alternatives to conventional chemotherapy.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    WHO. Tuberculosis Fact sheet N°104. (2012)

  2. 2.

    , & Tuberculosis: what we don’t know can, and does, hurt us. Science 328, 852–856 (2010)

  3. 3.

    , , & Bettering BCG: a tough task for a TB vaccine? Nature Med. 19, 410–411 (2013)

  4. 4.

    & Tuberculosis. Lancet 378, 57–72 (2011)

  5. 5.

    et al. Multidrug-resistant and extensively drug-resistant tuberculosis: a threat to global control of tuberculosis. Lancet 375, 1830–1843 (2010)

  6. 6.

    Fresh approaches to anti-infective therapies. Sci. Transl. Med. 4, 140sr142 (2012)

  7. 7.

    & Inflammation in tuberculosis: interactions, imbalances and interventions. Curr. Opin. Immunol. 25, 441–449 (2013)

  8. 8.

    et al. Innate and adaptive interferons suppress IL-1α and IL-1β production by distinct pulmonary myeloid subsets during Mycobacterium tuberculosis infection. Immunity 35, 1023–1034 (2011)

  9. 9.

    et al. Caspase-1 independent IL-1β production is critical for host resistance to Mycobacterium tuberculosis and does not require TLR signaling in vivo. J. Immunol. 184, 3326–3330 (2010)

  10. 10.

    , & Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nature Rev. Immunol. 8, 349–361 (2008)

  11. 11.

    et al. Host control of Mycobacterium tuberculosis is regulated by 5-lipoxygenase-dependent lipoxin production. J. Clin. Invest. 115, 1601–1606 (2005)

  12. 12.

    et al. Lipid mediators in innate immunity against tuberculosis: opposing roles of PGE2 and LXA4 in the induction of macrophage death. J. Exp. Med. 205, 2791–2801 (2008)

  13. 13.

    et al. Mycobacterium tuberculosis evades macrophage defenses by inhibiting plasma membrane repair. Nature Immunol. 10, 899–906 (2009)

  14. 14.

    et al. Compensatory prostaglandin E2 biosynthesis in cyclooxygenase 1 or 2 null cells. J. Exp. Med. 187, 517–523 (1998)

  15. 15.

    et al. Intranasal Poly-IC treatment exacerbates tuberculosis in mice through the pulmonary recruitment of a pathogen-permissive monocyte/macrophage population. J. Clin. Invest. 120, 1674–1682 (2010)

  16. 16.

    , , , & Antagonistic crosstalk between type I and II interferons and increased host susceptibility to bacterial infections. Virulence 1, 418–422 (2010)

  17. 17.

    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-α/β. Proc. Natl Acad. Sci. USA 98, 5752–5757 (2001)

  18. 18.

    , , & The type I IFN response to infection with Mycobacterium tuberculosis requires ESX-1-mediated secretion and contributes to pathogenesis. J. Immunol. 178, 3143–3152 (2007)

  19. 19.

    et al. The immune response in tuberculosis. Annu. Rev. Immunol. 31, 475–527 (2013)

  20. 20.

    et al. An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis. Nature 466, 973–977 (2010)

  21. 21.

    et al. Human gene expression profiles of susceptibility and resistance in tuberculosis. Genes Immun. 12, 15–22 (2011)

  22. 22.

    et al. Genome-wide expression profiling identifies type 1 interferon response pathways in active tuberculosis. PLoS ONE 7, e45839 (2012)

  23. 23.

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

  24. 24.

    et al. Increased release of interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha by bronchoalveolar cells lavaged from involved sites in pulmonary tuberculosis. Am. J. Respir. Crit. Care Med. 153, 799–804 (1996)

  25. 25.

    et al. Increased TNF-alpha, IL-1 beta and IL-6 levels in the bronchoalveolar lavage fluid with the upregulation of their mRNA in macrophages lavaged from patients with active pulmonary tuberculosis. Tuber. Lung. Dis. 79, 279–285 (1999)

  26. 26.

    et al. Nitric oxide modulates interleukin-1beta and tumor necrosis factor-alpha synthesis by alveolar macrophages in pulmonary tuberculosis. Am. J. Respir. Crit. Care Med. 161, 192–199 (2000)

  27. 27.

    & Nitric oxide modulates interleukin-1beta and tumour necrosis factor-alpha synthesis, and disease regression by alveolar macrophages in pulmonary tuberculosis. Respirology 6, 79–84 (2001)

  28. 28.

    , , , & Biomarker discovery by sparse canonical correlation analysis of complex clinical phenotypes of tuberculosis and malaria. PLOS Comput. Biol. 9, e1003018 (2013)

  29. 29.

    et al. The lta4h locus modulates susceptibility to mycobacterial infection in zebrafish and humans. Cell 140, 717–730 (2010)

  30. 30.

    et al. Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections. Cell 148, 434–446 (2012)

  31. 31.

    et al. Plasma heme oxygenase-1 levels distinguish latent or successfully treated human tuberculosis from active disease. PLoS ONE 8, e62618 (2013)

  32. 32.

    in Animal Tissue Techniques Ch. 20, 355 (, 1979)

  33. 33.

    et al. Influenza A virus impairs control of Mycobacterium tuberculosis co-infection through a type I interferon receptor dependent pathway. J. Infect. Dis. 209, 270–274 (2014)

Download references

Acknowledgements

This work was supported by the NIAID Intramural Research program and a Concept Acceleration Program-Award (K.D.M.-B., B.B.A. and A.S.) from DMID, NIAID. We are grateful to K. Elkins, S. Morris, M. Belcher as well as the NIAID ABSL3 support staff for facilitating our animal studies. We thank R. Chen, L. Goldfeder and Q. Gao for sharing their clinical trial expertise and research facilities, respectively. We also thank K. Kauffman, R. Thompson, S. Hieny, P. Dayal, D. Surman, L. Meng, Z. Li, L. Lifa, Q. Shen and Z. Huang for technical assistance, H. Boshoff for help with direct anti-mycobacterial activity assays and M. S. Jawahar, V. V. Banurekha and R. Sridhar for recruitment and clinical evaluation of patients in Chennai, India. We are grateful to F. Andrade Neto, H. Remold, K. Arora, J. Aliberti, M. Moayeri, P. Murphy, A. O’Garra, R. Germain and C. Serhan for discussion or critical reading of the manuscript. Finally, we thank the patients, volunteer participants, and clinical staff of the Tuberculosis department of Henan Chest Hospital in Zhengzhou, China and the Department of Clinical Research (NIRT) and Department of Thoracic Medicine (Government Stanley Medical Hospital) in Chennai, India for their participation in our clinical studies.

Author information

Affiliations

  1. Immunobiology Section, Laboratory of Parasitic Diseases (LPD), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA

    • Katrin D. Mayer-Barber
    • , Bruno B. Andrade
    • , Sandra D. Oland
    • , Eduardo P. Amaral
    •  & Alan Sher
  2. Department of Immunology, Biomedical Sciences Institutes, University of Sao Paulo, 05508-900 Sao Paulo, Brazil

    • Eduardo P. Amaral
  3. T Lymphocyte Biology Unit, LPD, NIAID, NIH, Bethesda, Maryland 20892, USA

    • Daniel L. Barber
  4. Tuberculosis Research Section, Laboratory of Clinical Infectious Disease, NIAID, NIH, Bethesda, Maryland 20892, USA

    • Jacqueline Gonzales
    • , Ying Cai
    • , Laura E. Via
    •  & Clifton E. Barry III
  5. Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA

    • Steven C. Derrick
  6. Henan Chest Hospital, 450003 Zhengzhou, China

    • Ruiru Shi
    • , Wang Wei
    •  & Xing Yuan
  7. NIH, International Center for Excellence in Research, 600 031 Chennai, India

    • Nathella Pavan Kumar
    •  & Subash Babu
  8. National Institute for Research in Tuberculosis (NIRT), 600 031 Chennai, India

    • Nathella Pavan Kumar
  9. Sino-US International Research Center for Tuberculosis, and Henan Public Health Center, 450003 Zhengzhou, China

    • Guolong Zhang
  10. Helminth Immunology Section, LPD, NIAID, NIH, Bethesda, Maryland 20892, USA

    • Subash Babu
  11. Clinical and Molecular Retrovirology Section, Laboratory of Immunoregulation, NIAID, NIH, Bethesda, Maryland 20892, USA

    • Marta Catalfamo
  12. Oncovir Inc., Washington, Washington DC 20008, USA

    • Andres M. Salazar

Authors

  1. Search for Katrin D. Mayer-Barber in:

  2. Search for Bruno B. Andrade in:

  3. Search for Sandra D. Oland in:

  4. Search for Eduardo P. Amaral in:

  5. Search for Daniel L. Barber in:

  6. Search for Jacqueline Gonzales in:

  7. Search for Steven C. Derrick in:

  8. Search for Ruiru Shi in:

  9. Search for Nathella Pavan Kumar in:

  10. Search for Wang Wei in:

  11. Search for Xing Yuan in:

  12. Search for Guolong Zhang in:

  13. Search for Ying Cai in:

  14. Search for Subash Babu in:

  15. Search for Marta Catalfamo in:

  16. Search for Andres M. Salazar in:

  17. Search for Laura E. Via in:

  18. Search for Clifton E. Barry III in:

  19. Search for Alan Sher in:

Contributions

K.D.M.-B. conceived the study, designed and performed experiments, analysed data and wrote the paper; B.B.A. performed experiments, analysed data and prepared the Indian cohort description; E.P.A. and D.L.B. performed experiments; S.D.O., J.G., S.C.D., N.P.K., Y.C., L.E.V., provided technical or analytical assistance; S.B. recruited, sampled and collected data about patients and provided access to samples from Indian cohort, M.C. provided healthy donor material, A.M.S. provided Hiltonol (pICLC); R.S., W.W., X.Y., G.Z., L.E.V. and C.E.B. conducted the Natural History Study in Zhengzhou, provided access to Chinese patient samples and the preparation of the Chinese cohort description, A.S. provided conceptual advice and wrote the paper and all authors approved the final manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Katrin D. Mayer-Barber.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Tables 1-8 containing clinically relevant data and parameters for clinical cohorts.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature13489

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.