TY - JOUR
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.
N1 - Funding Information:
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.
Publisher Copyright:
© 2018, The Author(s), under exclusive licence to Springer Nature Limited.
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85053693905&partnerID=8YFLogxK
U2 - 10.1038/s41564-018-0245-0
DO - 10.1038/s41564-018-0245-0
M3 - Letter
C2 - 30224802
AN - SCOPUS:85053693905
SN - 2058-5276
VL - 3
SP - 1099
EP - 1108
JO - Nature Microbiology
JF - Nature Microbiology
IS - 10
ER -