Mycobacterium tuberculosis carrying a rifampicin drug resistance mutation reprograms macrophage metabolism through cell wall lipid changes

Nicole C. Howard, Nancy D. Marin, Mushtaq Ahmed, Bruce A. Rosa, John Martin, Monika Bambouskova, Alexey Sergushichev, Ekaterina Loginicheva, Natalia Kurepina, Javier Rangel-Moreno, Liang Chen, Barry N. Kreiswirth, Robyn S. Klein, Joan Miquel Balada-Llasat, Jordi B. Torrelles, Gaya K. Amarasinghe, Makedonka Mitreva, Maxim N. Artyomov, Fong Fu Hsu, Barun MathemaShabaana A. Khader

Research output: Contribution to journalLetter

7 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1099-1108
Number of pages10
JournalNature Microbiology
Volume3
Issue number10
DOIs
StatePublished - Oct 1 2018

Fingerprint

Rifampin
Mycobacterium tuberculosis
Drug Resistance
Cell Wall
Macrophages
Lipids
Mutation
Multidrug-Resistant Tuberculosis
Pharmaceutical Preparations
Single Nucleotide Polymorphism
Tuberculosis
Interleukin-1 Type I Receptors
Poisons
Isoniazid
Glycolysis
Interleukin-1
Interferons
Disease Outbreaks
Mortality

All Science Journal Classification (ASJC) codes

  • Applied Microbiology and Biotechnology
  • Microbiology (medical)
  • Genetics
  • Cell Biology
  • Microbiology
  • Immunology

Cite this

Howard, Nicole C. ; Marin, Nancy D. ; Ahmed, Mushtaq ; Rosa, Bruce A. ; Martin, John ; Bambouskova, Monika ; Sergushichev, Alexey ; Loginicheva, Ekaterina ; Kurepina, Natalia ; Rangel-Moreno, Javier ; Chen, Liang ; Kreiswirth, Barry N. ; Klein, Robyn S. ; Balada-Llasat, Joan Miquel ; Torrelles, Jordi B. ; Amarasinghe, Gaya K. ; Mitreva, Makedonka ; Artyomov, Maxim N. ; Hsu, Fong Fu ; Mathema, Barun ; Khader, Shabaana A. / Mycobacterium tuberculosis carrying a rifampicin drug resistance mutation reprograms macrophage metabolism through cell wall lipid changes. In: Nature Microbiology. 2018 ; Vol. 3, No. 10. pp. 1099-1108.
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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.",
author = "Howard, {Nicole C.} and Marin, {Nancy D.} and Mushtaq Ahmed and Rosa, {Bruce A.} and John Martin and Monika Bambouskova and Alexey Sergushichev and Ekaterina Loginicheva and Natalia Kurepina and Javier Rangel-Moreno and Liang Chen and Kreiswirth, {Barry N.} and Klein, {Robyn S.} and Balada-Llasat, {Joan Miquel} and Torrelles, {Jordi B.} and Amarasinghe, {Gaya K.} and Makedonka Mitreva and Artyomov, {Maxim N.} and Hsu, {Fong Fu} and Barun Mathema and Khader, {Shabaana A.}",
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Howard, NC, Marin, ND, Ahmed, M, Rosa, BA, Martin, J, Bambouskova, M, Sergushichev, A, Loginicheva, E, Kurepina, N, Rangel-Moreno, J, Chen, L, Kreiswirth, BN, Klein, RS, Balada-Llasat, JM, Torrelles, JB, Amarasinghe, GK, Mitreva, M, Artyomov, MN, Hsu, FF, Mathema, B & Khader, SA 2018, 'Mycobacterium tuberculosis carrying a rifampicin drug resistance mutation reprograms macrophage metabolism through cell wall lipid changes', Nature Microbiology, vol. 3, no. 10, pp. 1099-1108. https://doi.org/10.1038/s41564-018-0245-0

Mycobacterium tuberculosis carrying a rifampicin drug resistance mutation reprograms macrophage metabolism through cell wall lipid changes. / Howard, Nicole C.; Marin, Nancy D.; Ahmed, Mushtaq; Rosa, Bruce A.; Martin, John; Bambouskova, Monika; Sergushichev, Alexey; Loginicheva, Ekaterina; Kurepina, Natalia; Rangel-Moreno, Javier; Chen, Liang; Kreiswirth, Barry N.; Klein, Robyn S.; Balada-Llasat, Joan Miquel; Torrelles, Jordi B.; Amarasinghe, Gaya K.; Mitreva, Makedonka; Artyomov, Maxim N.; Hsu, Fong Fu; Mathema, Barun; Khader, Shabaana A.

In: Nature Microbiology, Vol. 3, No. 10, 01.10.2018, p. 1099-1108.

Research output: Contribution to journalLetter

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T1 - Mycobacterium tuberculosis carrying a rifampicin drug resistance mutation reprograms macrophage metabolism through cell wall lipid changes

AU - Howard, Nicole C.

AU - Marin, Nancy D.

AU - Ahmed, Mushtaq

AU - Rosa, Bruce A.

AU - Martin, John

AU - Bambouskova, Monika

AU - Sergushichev, Alexey

AU - Loginicheva, Ekaterina

AU - Kurepina, Natalia

AU - Rangel-Moreno, Javier

AU - Chen, Liang

AU - Kreiswirth, Barry N.

AU - Klein, Robyn S.

AU - Balada-Llasat, Joan Miquel

AU - Torrelles, Jordi B.

AU - Amarasinghe, Gaya K.

AU - Mitreva, Makedonka

AU - Artyomov, Maxim N.

AU - Hsu, Fong Fu

AU - Mathema, Barun

AU - Khader, Shabaana A.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - 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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