Abstract
The pathogenic success of Mycobacterium tuberculosis (Mtb) is tightly linked to its ability to recalibrate host metabolic processes in infected host macrophages. Since changes in cellular metabolic intermediates or pathways also affect macrophage function in response to pathogens, we sought to analyse specific metabolic alterations induced by Mtb infection. Stimulation of macrophages with Mtb lysate or lipopolysaccharide (LPS) induced a relative increase in glycolysis versus oxidative phosphorylation. Cellular metabolomics revealed that Mtb infection induced a distinct metabolic profile compared to LPS in both M1 and M2 macrophages. Specifically, Mtb infection resulted in elevated intracellular levels of nicotinamide adenine dinucleotide (NAD+), creatine, creatine phosphate and glutathione compared to uninfected control macrophages. Correspondingly, RNA-sequencing datasets showed altered gene expression of key metabolic enzymes involved in NAD+, creatine, glucose and glutamine metabolism (e.g NAMPT, SLC6A8, HK2) in Mtb-infected M2 macrophages. These findings demonstrate clear modulation of host macrophage metabolic pathways by Mtb infection.
Highlights
Mycobacterium tuberculosis (Mtb) is the causative pathogen of tuberculosis (TB) and responsible for over a million deaths annually[1]
Mtb lysate induced similar tendencies for both extracellular acidification rate (ECAR)/oxygen consumption rate (OCR) ratio (Fig. 1C,D) and spare respiratory capacity (SRC) (Fig. 1E), the magnitude of this effect was less pronounced compared to LPS
While we were able to validate that activation with LPS and Mtb lysate resulted in a relative shift toward increased glycolysis in primary macrophages, many of the published findings in the literature have yet to be translated to infections of primary human cells with live pathogens
Summary
Mycobacterium tuberculosis (Mtb) is the causative pathogen of tuberculosis (TB) and responsible for over a million deaths annually[1]. Considering the importance of metabolic adaptations for Mtb killing and survival, several studies aimed to dissect the precise impact of the bacterium on macrophage metabolism by cellular metabolomics[29,30,31] These relied on phorbol 12-myristate 13-acetate (PMA)-activated macrophage-like THP-1 cells as a model for macrophage infection, which significantly differ from primary macrophages in terms of polarization and response to stimuli[32,33]. To address this critical gap in knowledge, we have here studied the effect of Mtb infection on primary human macrophage metabolism using untargeted liquid chromatography-mass spectrometry (LC-MS) metabolomics and targeted 1H-nuclear magnetic resonance (NMR) spectroscopy[34]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
