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.

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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


  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


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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.

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

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