Host-directed therapies for tuberculosis: quantitative systems pharmacology approaches

Mehta, Krina; Spaink, Herman P.; Ottenhoff, Tom H. M.; Graaf, Piet H. van der; Hasselt, Johan G. C. van

doi:10.1016/j.tips.2021.11.016

Cited by 8 publications

(12 citation statements)

References 67 publications

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“…The fine balance between levels of pro- and anti-inflammatory cytokines is an important attribute of the host-pathogen interactions affecting the overall disease outcome [3]. For example, high levels of pro-inflammatory cytokines may be associated with increased inflammation and tissue damage but can also reduce immune-mediated bactericidal activity [24,38].…”

Section: Discussionmentioning

confidence: 99%

“…Metformin adjunctive therapy in diabetic TB patients was found to be associated with an improved therapy success rate and lowered mortality [8,9]. The translation of experimental findings towards patients and subsequent optimal and rational design of HDT treatment strategies is challenged by the complex nature of the host-pathogen interactions [3].…”

Section: Introductionmentioning

confidence: 99%

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Quantitative Systems Pharmacology Modeling Framework of Autophagy in Tuberculosis: Application to Adjunctive Metformin Host-Directed Therapy

Mehta

Guo

Wallis

et al. 2022

Preprint

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Background: Quantitative systems pharmacology (QSP) modeling of the host-immune response against Mtb can inform rational design of host-directed therapies (HDTs). We aimed to develop a QSP framework to evaluate the effects of metformin-associated autophagy-induction in combination with antibiotics. Methods: A QSP framework for autophagy was developed by extending a model for host-immune response to include AMPK-mTOR-autophagy signalling. This model was combined with pharmacokinetic-pharmacodynamic models for metformin and antibiotics against Mtb. We compared the model predictions to mice infection experiments, and derived predictions for pathogen and host-associated dynamics in humans treated with metformin in combination with antibiotics. Results: The model adequately captured the observed bacterial load dynamics in mice Mtb infection models treated with metformin. Simulations for adjunctive metformin therapy in newly diagnosed patients suggested a limited yet dose-dependent effect of metformin on reducing the intracellular bacterial load and selected pro-inflammatory cytokines. Our predictions suggest that metformin may provide beneficiary effects when overall bacterial load, or extracellular-to-intracellular bacterial ratio is low, either early after infection or late during antibiotic treatment. Conclusions: We present the first QSP framework for HDTs against Mtb, linking cellular-level autophagy effects to disease progression. This framework may be extended to guide design of HDTs against Mtb.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Quantitative Systems Pharmacology Modeling Framework of Autophagy in Tuberculosis: Application to Adjunctive Metformin Host-Directed Therapy

Mehta

Guo

Wallis

et al. 2022

Preprint

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“…M. tuberculosis ΔleuD ΔpanCD (Bleupan) double auxotroph strain (5) (gift from Dr Bill Jacobs) was transduced with pSMT12-mCherry or pSMT12-GFP (gifts from Dr Lalita Ramakrishnan, Cambridge, UK) or pSMT1-LuxAB-GFP , and grown in Middlebrook 7H9 broth containing 0.5% glycerol, 0.05% Tween 80 and 10% oleic acid– albumin–dextrose–catalase enrichment (OADC) (BD Bioscience), 0.05 mg/ml L-leucine ( Sigma-Aldrich ), 0.024 mg/ml calcium pantothenate (Sigma-Aldrich). When necessary, 50 μg/ml hygromycin B ( EMD Millipore ), 40 μg/ml kanamycin or 50 μg/mL zeocin ( Alfa Aesar ) were added to cultures.…”

Section: Methodsmentioning

confidence: 99%

“…Tuberculosis (TB), a disease caused by mycobacteria of the Mtb complex (MTBC), remains a major global threat to human health, with an estimated third of the World population at one time exposed (1), over 1.3 million deaths recorded per year (2), and growing rates seen for multidrug resistant (MDR) and extensively drug resistant (XDR) (3,4), Increasing antibiotic resistance and long treatment durations have motivated the search for druggable innate immune pathways that could be pharmacologically stimulated to deliver host-directed therapy (5–7).…”

Section: Main Textmentioning

confidence: 99%

Phagosomal RNA sensing through TLR8 controls susceptibility to tuberculosis

Maserumule

Passemar

et al. 2022

Preprint

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Genetic determinants of susceptibility to Mycobacterium tuberculosis (Mtb) are poorly understood but could provide insights into critical pathways involved in infection, informing host-directed therapies and enabling risk stratification at individual and population levels. Through a genome-wide forward genetic screen, we identify the Toll-like Receptor 8 (TLR8), as a key regulator of intracellular killing of Mtb. Pharmacological TLR8 activation enhances killing of phylogenetically diverse clinical isolates of drug-susceptible and multidrug-resistant Mtb by macrophages and during in vivo infection in mice. TLR8 is activated by phagosomal mycobacterial RNA released by extracellular membrane vesicles, and enhances xenophagy-dependent Mtb killing. We find that the TLR8 variant, M1V, common in far eastern populations, enhances intracellular killing of Mtb through preferential signal-dependent trafficking to phagosomes. TLR8 signalling may therefore both regulate susceptibility to tuberculosis and provide novel drug targets.Single sentence summaryRNA released from Mycobacterium tuberculosis in the macrophage phagosome is sensed by the pattern recognition receptor TLR8 controlling host susceptibility to tuberculosis and revealing a druggable pathway for host-directed therapy.

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“…Bedaquiline activates the autophagy and anti-bacterial ability of macrophages via reducing glycolytic flux and enhancing phosphatidylinositol synthesis [ 19 ]. The inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) or 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase reduces cholesterol synthesis in macrophages to accelerate the clearance of engulfed M. tuberculosis [ 20 ]. Generally speaking, host-directed therapies are less likely to place selective pressure on pathogens, and thus these host-directed therapies, in combination with pathogen-directed drugs, are expected to enhance efficacy.…”

Section: Introductionmentioning

confidence: 99%

Reconstructed Genome-Scale Metabolic Model Characterizes Adaptive Metabolic Flux Changes in Peripheral Blood Mononuclear Cells in Severe COVID-19 Patients

Tang

Liu

Ruan

et al. 2022

IJMS

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Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) poses a mortal threat to human health. The elucidation of the relationship between peripheral immune cells and the development of inflammation is essential for revealing the pathogenic mechanism of COVID-19 and developing related antiviral drugs. The immune cell metabolism-targeting therapies exhibit a desirable anti-inflammatory effect in some treatment cases. In this study, based on differentially expressed gene (DEG) analysis, a genome-scale metabolic model (GSMM) was reconstructed by integrating transcriptome data to characterize the adaptive metabolic changes in peripheral blood mononuclear cells (PBMCs) in severe COVID-19 patients. Differential flux analysis revealed that metabolic changes such as enhanced aerobic glycolysis, impaired oxidative phosphorylation, fluctuating biogenesis of lipids, vitamins (folate and retinol), and nucleotides played important roles in the inflammation adaptation of PBMCs. Moreover, the main metabolic enzymes such as the solute carrier (SLC) family 2 member 3 (SLC2A3) and fatty acid synthase (FASN), responsible for the reactions with large differential fluxes, were identified as potential therapeutic targets. Our results revealed the inflammation regulation potentials of partial metabolic reactions with differential fluxes and their metabolites. This study provides a reference for developing potential PBMC metabolism-targeting therapy strategies against COVID-19.

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Host-directed therapies for tuberculosis: quantitative systems pharmacology approaches

Cited by 8 publications

References 67 publications

Quantitative Systems Pharmacology Modeling Framework of Autophagy in Tuberculosis: Application to Adjunctive Metformin Host-Directed Therapy

Quantitative Systems Pharmacology Modeling Framework of Autophagy in Tuberculosis: Application to Adjunctive Metformin Host-Directed Therapy

Phagosomal RNA sensing through TLR8 controls susceptibility to tuberculosis

Reconstructed Genome-Scale Metabolic Model Characterizes Adaptive Metabolic Flux Changes in Peripheral Blood Mononuclear Cells in Severe COVID-19 Patients

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