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
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
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.
Extended data figures
This file contains Supplementary Tables 1-8 containing clinically relevant data and parameters for clinical cohorts.
About this article
Molecular Cell (2019)