Abstract

Tuberculosis is a significant global health threat, with one-third of the world’s population infected with its causative agent Mycobacterium tuberculosis (Mtb). The emergence of multidrug-resistant (MDR) Mtb that is resistant to the frontline anti-tubercular drugs rifampicin and isoniazid forces treatment with toxic second-line drugs. Currently, ~4% of new and ~21% of previously treated tuberculosis cases are either rifampicin-drug-resistant or MDR Mtb infections1. The specific molecular host–pathogen interactions mediating the rapid worldwide spread of MDR Mtb strains remain poorly understood. W-Beijing Mtb strains are highly prevalent throughout the world and associated with increased drug resistance2. In the early 1990s, closely related MDR W-Beijing Mtb strains (W strains) were identified in large institutional outbreaks in New York City and caused high mortality rates3. The production of interleukin-1β (IL-1β) by macrophages coincides with the shift towards aerobic glycolysis, a metabolic process that mediates protection against drug-susceptible Mtb4. Here, using a collection of MDR W-Mtb strains, we demonstrate that the overexpression of Mtb cell wall lipids, phthiocerol dimycocerosates, bypasses the interleukin 1 receptor, type I (IL-1R1) signalling pathway, instead driving the induction of interferon-β (IFN-β) to reprogram macrophage metabolism. Importantly, Mtb carrying a drug resistance-conferring single nucleotide polymorphism in rpoB (H445Y)5 can modulate host macrophage metabolic reprogramming. These findings transform our mechanistic understanding of how emerging MDR Mtb strains may acquire drug resistance single nucleotide polymorphisms, thereby altering Mtb surface lipid expression and modulating host macrophage metabolic reprogramming.

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Data availability

All relevant data are available from the authors. DNA sequencing data have been submitted under BioProject ID PRJNA353361. RNA sequencing data have been deposited in the Gene Expression Omnibus (GEO) database (accession number GSE115495).

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Change history

  • 16 October 2018

    In the version of this Letter originally published, in Fig. 2d, in the third graph, the label for the y axis was incorrect as ‘TNF-α (pg ml–1)’; it should have read ‘IL-1β (pg ml–1)’. This has now been corrected.

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Acknowledgements

This work was supported by Washington University in St. Louis; NIH grants HL105427, AI123780 and AI111914 to S.A.K. and NIH/NHLBI T32 HL007317-37 to N.C.H. A.S. was supported by the Ministry of Education and Science of the Russian Federation (Project 2.3300.2017/4.6). J.R.-M. was supported by funds from the Department of Medicine, University of Rochester and U19 AI91036. The protein identifications and LC/MS analyses were generated at the Washington University Proteomics Shared Resource (WU-PSR). The WU-PSR is supported by the WU Institute of Clinical and Translational Sciences (grant no. NCATS UL1 TR000448), the WU Mass Spectrometry Research Resource (grant nos. NIGMS P41 GM103422, P60-DK-20579, P30-DK56341) and the Siteman Comprehensive Cancer Center (grant no. NCI P30 CA091842). The authors thank L. Schuettpelz (Washington University in St. Louis), U. Nagarajan (University of North Carolina, Chapel Hill), J.H. Russell (Washington University in St. Louis) and H.W. Virgin IV (Washington University in St. Louis) for generously providing mice, J.M. Scordo (Texas Biomed) and R. Domingo-Gonzalez (Washington University in St. Louis) for technical help and S. Squires and L. Lu (Washington University in St. Louis) for animal breeding. We thank T. Stappenbeck and J. Phillips (Washington University in St. Louis) for critical reading of the manuscript.

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Affiliations

  1. Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA

    • Nicole C. Howard
    • , Nancy D. Marin
    • , Mushtaq Ahmed
    •  & Shabaana A. Khader
  2. Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA

    • Bruce A. Rosa
    • , John Martin
    • , Robyn S. Klein
    • , Makedonka Mitreva
    •  & Fong-Fu Hsu
  3. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA

    • Monika Bambouskova
    • , Ekaterina Loginicheva
    • , Gaya K. Amarasinghe
    •  & Maxim N. Artyomov
  4. Computer Technologies Department, ITMO University, Saint Petersburg, Russia

    • Alexey Sergushichev
  5. Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, NJ, USA

    • Natalia Kurepina
    • , Liang Chen
    •  & Barry N. Kreiswirth
  6. Division of Allergy/Immunology and Rheumatology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA

    • Javier Rangel-Moreno
  7. Department of Pathology, The Ohio State University, Columbus, OH, USA

    • Joan-Miquel Balada-Llasat
  8. Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, USA

    • Jordi B. Torrelles
  9. Texas Biomedical Research Institute, San Antonio, TX, USA

    • Jordi B. Torrelles
  10. Department of Epidemiology, Columbia University Mailman School of Public Health, New York, NY, USA

    • Barun Mathema

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Contributions

N.C.H., B.M., R.S.K., M.N.A., G.K.A. and S.A.K. conceived the experiments. N.C.H., N.D.M., M.A., B.A.R., J.M., M.B., A.S., E.L., N.K., J.R-M., J.B.T., F.-F.H. and J.-M.B.-L. carried out the experiments. L.C., B.N.K., B.M., S.A.K., M.N.A., R.S.K., J.B.T. provided reagents and Mtb strains. N.C.H., N.D.M., M.A., B.A.R., J.M., M.B., A.S., E.L., N.K., J.R.-M., J.B.T., F.-F.H., M.M., M.N.A., B.M. and S.A.K. conducted the analyses. N.C.H. and S.A.K. wrote the paper. All the authors edited the paper and S.A.K. provided funding and overall project supervision and administration.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Shabaana A. Khader.

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DOI

https://doi.org/10.1038/s41564-018-0245-0

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