Abstract
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.
Highlights
The use of antimicrobials for the treatment of tuberculosis (TB) has been the mainstay for almost 50 years
We show that TB antimicrobials differentially alter both oxidative phosphorylation (OXPHOS) and glycolysis in unstimulated, iH37Rv-Mycobacterium tuberculosis (Mtb) and LPS-stimulated Human monocyte-derived macrophages (hMDMs), with some of these observations linked with alterations in mitochondrial function
TB antimicrobials optimally elicit direct bactericidal effects on mycobacteria, both in cellular and axenic models of TB infection [5,22,23,24,25,26,27]. Examining how these antimicrobials affect immunometabolic profiles and mitochondrial function in parallel could offer some insight into how these antimicrobials potentially affect immune function [7], in patients with active TB who are subjected to long-term antimicrobial treatment regimens
Summary
The use of antimicrobials for the treatment of tuberculosis (TB) has been the mainstay for almost 50 years now. The eradication of TB in patients with drug-sensitive TB is quite efficacious, treatment for patients with drug-resistant TB involves a much longer, gruelling, and complex drug regimen, often involving the administration of numerous toxic antimicrobials. This necessitates the need to identify therapies to help to improve the current state-of-the-art treatments. A significant amount of attention has turned to the use of host-directed therapies to modulate immune responses in infected host immune cells [1] These strategies have been hypothesized to work through augmenting anti-inflammatory [2,3], pro-inflammatory [2,4,5,6,7], and immunometabolic processes [4,6,7,8]. The literature highlights some contradictory findings across different cell types and gives us some insight into how TB antimicrobials could affect a variety of cellular processes, while highlighting the need for more studies that detail and characterise these immunomodulatory effects, in primary human cell models
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