The Effect of Tuberculosis Antimicrobials on the Immunometabolic Profiles of Primary Human Macrophages Stimulated with <i>Mycobacterium tuberculosis</i>

Tuberculosis (TB) remains a global health challenge. Patients with drug-sensitive and drug-resistant TB undergo long, arduous, and complex treatment regimens, often involving multiple antimicrobials. While these drugs were initially implemented based on their bactericidal effects, some studies show...

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Autores principales:	Christina Cahill, Dónal J. Cox, Fiona O’Connell, Sharee A. Basdeo, Karl M. Gogan, Cilian Ó’Maoldomhnaigh, Jacintha O’Sullivan, Joseph Keane, James J. Phelan
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	tuberculosis drug-resistant tuberculosis host-directed therapy antimicrobials glycolysis oxidative phosphorylation Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/890985290cbb45fd9a7aa24df19e0be4
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spelling	oai:doaj.org-article:890985290cbb45fd9a7aa24df19e0be42021-11-25T17:54:09ZThe Effect of Tuberculosis Antimicrobials on the Immunometabolic Profiles of Primary Human Macrophages Stimulated with <i>Mycobacterium tuberculosis</i>10.3390/ijms2222121891422-00671661-6596https://doaj.org/article/890985290cbb45fd9a7aa24df19e0be42021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12189https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Tuberculosis (TB) remains a global health challenge. Patients with drug-sensitive and drug-resistant TB undergo long, arduous, and complex treatment regimens, often involving multiple antimicrobials. While these drugs were initially implemented based on their bactericidal effects, some studies show that TB antimicrobials can also directly affect cells of the immune system, altering their immune function. As use of these antimicrobials has been the mainstay of TB therapy for over fifty years now, it is more important than ever to understand how these antimicrobials affect key pathways of the immune system. One such central pathway, which underpins the immune response to a variety of infections, is immunometabolism, namely glycolysis and oxidative phosphorylation (OXPHOS). We hypothesise that in addition to their direct bactericidal effect on <i>Mycobacterium tuberculosis</i> (Mtb), current TB antimicrobials can modulate immunometabolic profiles and alter mitochondrial function in primary human macrophages. Human monocyte-derived macrophages (hMDMs) were differentiated from PBMCs isolated from healthy blood donors, and treated with four first-line and six second-line TB antimicrobials three hours post stimulation with either iH37Rv-Mtb or lipopolysaccharide (LPS). 24 h post stimulation, baseline metabolism and mitochondrial function were determined using the Seahorse Extracellular Flux Analyser. The effect of these antimicrobials on cytokine and chemokine production was also assayed using Meso Scale Discovery Multi-Array technology. We show that some of the TB antimicrobials tested can significantly alter OXPHOS and glycolysis in uninfected, iH37Rv-Mtb, and LPS-stimulated hMDMs. We also demonstrate how these antimicrobial-induced immunometabolic effects are linked with alterations in mitochondrial function. Our results show that TB antimicrobials, specifically clofazimine, can modify host immunometabolism and mitochondrial function. Moreover, clofazimine significantly increased the production of IL-6 in human macrophages that were stimulated with iH37Rv-Mtb. This provides further insight into the use of some of these TB antimicrobials as potential host-directed therapies in patients with early and active disease, which could help to inform TB treatment strategies in the future.Christina CahillDónal J. CoxFiona O’ConnellSharee A. BasdeoKarl M. GoganCilian Ó’MaoldomhnaighJacintha O’SullivanJoseph KeaneJames J. PhelanMDPI AGarticletuberculosisdrug-resistant tuberculosishost-directed therapyantimicrobialsglycolysisoxidative phosphorylationBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12189, p 12189 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	tuberculosis drug-resistant tuberculosis host-directed therapy antimicrobials glycolysis oxidative phosphorylation Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	tuberculosis drug-resistant tuberculosis host-directed therapy antimicrobials glycolysis oxidative phosphorylation Biology (General) QH301-705.5 Chemistry QD1-999 Christina Cahill Dónal J. Cox Fiona O’Connell Sharee A. Basdeo Karl M. Gogan Cilian Ó’Maoldomhnaigh Jacintha O’Sullivan Joseph Keane James J. Phelan The Effect of Tuberculosis Antimicrobials on the Immunometabolic Profiles of Primary Human Macrophages Stimulated with <i>Mycobacterium tuberculosis</i>
description	Tuberculosis (TB) remains a global health challenge. Patients with drug-sensitive and drug-resistant TB undergo long, arduous, and complex treatment regimens, often involving multiple antimicrobials. While these drugs were initially implemented based on their bactericidal effects, some studies show that TB antimicrobials can also directly affect cells of the immune system, altering their immune function. As use of these antimicrobials has been the mainstay of TB therapy for over fifty years now, it is more important than ever to understand how these antimicrobials affect key pathways of the immune system. One such central pathway, which underpins the immune response to a variety of infections, is immunometabolism, namely glycolysis and oxidative phosphorylation (OXPHOS). We hypothesise that in addition to their direct bactericidal effect on <i>Mycobacterium tuberculosis</i> (Mtb), current TB antimicrobials can modulate immunometabolic profiles and alter mitochondrial function in primary human macrophages. Human monocyte-derived macrophages (hMDMs) were differentiated from PBMCs isolated from healthy blood donors, and treated with four first-line and six second-line TB antimicrobials three hours post stimulation with either iH37Rv-Mtb or lipopolysaccharide (LPS). 24 h post stimulation, baseline metabolism and mitochondrial function were determined using the Seahorse Extracellular Flux Analyser. The effect of these antimicrobials on cytokine and chemokine production was also assayed using Meso Scale Discovery Multi-Array technology. We show that some of the TB antimicrobials tested can significantly alter OXPHOS and glycolysis in uninfected, iH37Rv-Mtb, and LPS-stimulated hMDMs. We also demonstrate how these antimicrobial-induced immunometabolic effects are linked with alterations in mitochondrial function. Our results show that TB antimicrobials, specifically clofazimine, can modify host immunometabolism and mitochondrial function. Moreover, clofazimine significantly increased the production of IL-6 in human macrophages that were stimulated with iH37Rv-Mtb. This provides further insight into the use of some of these TB antimicrobials as potential host-directed therapies in patients with early and active disease, which could help to inform TB treatment strategies in the future.
format	article
author	Christina Cahill Dónal J. Cox Fiona O’Connell Sharee A. Basdeo Karl M. Gogan Cilian Ó’Maoldomhnaigh Jacintha O’Sullivan Joseph Keane James J. Phelan
author_facet	Christina Cahill Dónal J. Cox Fiona O’Connell Sharee A. Basdeo Karl M. Gogan Cilian Ó’Maoldomhnaigh Jacintha O’Sullivan Joseph Keane James J. Phelan
author_sort	Christina Cahill
title	The Effect of Tuberculosis Antimicrobials on the Immunometabolic Profiles of Primary Human Macrophages Stimulated with <i>Mycobacterium tuberculosis</i>
title_short	The Effect of Tuberculosis Antimicrobials on the Immunometabolic Profiles of Primary Human Macrophages Stimulated with <i>Mycobacterium tuberculosis</i>
title_full	The Effect of Tuberculosis Antimicrobials on the Immunometabolic Profiles of Primary Human Macrophages Stimulated with <i>Mycobacterium tuberculosis</i>
title_fullStr	The Effect of Tuberculosis Antimicrobials on the Immunometabolic Profiles of Primary Human Macrophages Stimulated with <i>Mycobacterium tuberculosis</i>
title_full_unstemmed	The Effect of Tuberculosis Antimicrobials on the Immunometabolic Profiles of Primary Human Macrophages Stimulated with <i>Mycobacterium tuberculosis</i>
title_sort	effect of tuberculosis antimicrobials on the immunometabolic profiles of primary human macrophages stimulated with <i>mycobacterium tuberculosis</i>
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/890985290cbb45fd9a7aa24df19e0be4
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The Effect of Tuberculosis Antimicrobials on the Immunometabolic Profiles of Primary Human Macrophages Stimulated with <i>Mycobacterium tuberculosis</i>

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