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

Autor: Fiona O'Connell, Christina Cahill, James J. Phelan, Joseph Keane, Donal J. Cox, Jacintha O'Sullivan, Cilian Ó'Maoldomhnaigh, Sharee A. Basdeo, Karl M. Gogan
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Lipopolysaccharides
Chemokine
Lipopolysaccharide
medicine.medical_treatment
Antitubercular Agents
bioenergetics
Clofazimine
chemistry.chemical_compound
Biology (General)
Spectroscopy
biology
lipopolysaccharide
General Medicine
glycolysis
Computer Science Applications
Mitochondria
Chemistry
Cytokine
tuberculosis
Cytokines
medicine.drug
Tuberculosis
QH301-705.5
Primary Cell Culture
oxidative phosphorylation
Peripheral blood mononuclear cell
Catalysis
Article
antimicrobials
host-directed therapy
Inorganic Chemistry
Mycobacterium tuberculosis
Immune system
mitochondrial function
medicine
Humans
Physical and Theoretical Chemistry
Molecular Biology
QD1-999
business.industry
drug-resistant tuberculosis
Macrophages
Organic Chemistry
medicine.disease
biology.organism_classification
chemistry
Immunology
biology.protein
business
Zdroj: International Journal of Molecular Sciences
International Journal of Molecular Sciences, Vol 22, Iss 12189, p 12189 (2021)
Volume 22
Issue 22
ISSN: 1422-0067
Popis: 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 Mycobacterium tuberculosis (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.
Databáze: OpenAIRE
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