The Effect of Tuberculosis Antimicrobials on the Immunometabolic Profiles of Primary Human Macrophages Stimulated with Mycobacterium tuberculosis
Abstract
:1. Introduction
2. Results
2.1. TB Antimicrobials Differentially Affect Glycolysis and Oxidative Phosphorylation Levels in Unstimulated, iH37Rv-Mtb- and LPS-Stimulated hMDMs
2.2. Clofazimine Alters Mitochondrial Coupling Efficacy and Protein Leak in Primary hMDMs Stimulated with Mtb
2.3. TB Antimicrobials Differentially Affect Levels of Secreted Cytokines and Chemokines in Unstimulated, iH37Rv-Mtb Stimulated and LPS-Stimulated hMDMs
3. Discussion
4. Materials and Methods
4.1. hMDM Cell Culture
4.2. Stimulation of hMDMs with iH37Rv-Mtb
4.3. Estimating Cell Number and Cell Viability Using Crystal Violet and Propidium Iodide (PI) Based Cell Exclusion Assays
4.4. Characterizing the Effect of Tuberculosis Antimicrobials on Metabolism Profiles and Mitochondrial Function Utilizing the Seahorse XFe24 Analyzer
4.5. Ex Vivo MSD Multiplex ELISA Analysis
4.6. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Drug Name | Abbreviation | Clinical Use | In Vitro Solvent | Mechanism of Action | Known Effects on Eukaryotic Cells |
---|---|---|---|---|---|
Ethambutol | EMB | First-line | dH2O | Functions by obstructing the formation of cell wall | Inhibits complex IV and OXPHOS in human fibroblasts [12] |
Isoniazid | INH | First-line | dH2O | Inhibits mycolic acid synthesis; interferes with cell wall synthesis | Reduces complex I-III activity & increases ROS and lipid peroxidation in rat mitochondria [13] and alters murine mitochondria [14] |
Pyrazinamide | PYZ | First-line | dH2O | Interferes with the bacteriums’ ability to synthesize new fatty acids (required for growth and replication) | Associated with increased ROS production in zebrafish larvae [15] |
Rifampicin | RIF | First-line | dH2O | Inhibits bacterial DNA-dependent RNA synthesis | Alters structure of mitochondria resulting in excessive ROS and release of cyto-chrome c [16] and alters murine mitpochondria [14] |
Amikacin | AMK | Second-line | dH2O | Interferes with mRNA binding (interferes with bacterial growth) | Unknown effects on eukaryotic cells [9] |
Bedaquiline | BDQ | Second-line | DMSO | Inhibits the proton pump of mycobacterial ATP synthase (essential for ATP production) | Inhibits the mitochondrial transport chain in rat models [17], reduces mitochondrial membrane potential and increases ROS production in human breast cancer cells [18] |
Clofazimine | CLO | Second-line | DMSO | Blocks the template function of DNA, inhibiting proliferation | CLO increases glycolysis in human non-small-cell bronchial-carcinoma cells [19] |
Cycloserine | CYS | Second-line | dH2O | Inhibits cell-wall biosynthesis | Unknown effects on eukaryotic cells [9] |
Linezolid | LIN | Second-line | DMSO | Inhibits bacterial protein synthesis | Decreases protein levels and the enzymatic activity of various mitochondrial complexes [20] |
Moxifloxacin | MOX | Second-line | dH2O | Blocks bacterial DNA replication | Exhibits anti-inflammatory effects in human THP-1 cells [21] |
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Cahill, C.; Cox, D.J.; O’Connell, F.; Basdeo, S.A.; Gogan, K.M.; Ó’Maoldomhnaigh, C.; O’Sullivan, J.; Keane, J.; Phelan, J.J. The Effect of Tuberculosis Antimicrobials on the Immunometabolic Profiles of Primary Human Macrophages Stimulated with Mycobacterium tuberculosis. Int. J. Mol. Sci. 2021, 22, 12189. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212189
Cahill C, Cox DJ, O’Connell F, Basdeo SA, Gogan KM, Ó’Maoldomhnaigh C, O’Sullivan J, Keane J, Phelan JJ. The Effect of Tuberculosis Antimicrobials on the Immunometabolic Profiles of Primary Human Macrophages Stimulated with Mycobacterium tuberculosis. International Journal of Molecular Sciences. 2021; 22(22):12189. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212189
Chicago/Turabian StyleCahill, Christina, Dónal J. Cox, Fiona O’Connell, Sharee A. Basdeo, Karl M. Gogan, Cilian Ó’Maoldomhnaigh, Jacintha O’Sullivan, Joseph Keane, and James J. Phelan. 2021. "The Effect of Tuberculosis Antimicrobials on the Immunometabolic Profiles of Primary Human Macrophages Stimulated with Mycobacterium tuberculosis" International Journal of Molecular Sciences 22, no. 22: 12189. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212189