Using metabolomics to dissect host–parasite interactions

Kloehn, Joachim; Blume, Martin; Cobbold, Simon A.; Saunders, Eleanor; Dagley, MJ; McConville, MJ

doi:10.1016/j.mib.2016.04.019

Cited by 39 publications

(34 citation statements)

References 49 publications

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“…Host-parasite interactions are multifaceted involving several factors that allow pathogens to evade the immune system and replicate [1,2]. In response to pathogens, immune cells undergo a wide range of phenotypical alterations, particularly in their metabolism, to optimize their immune effector functions.…”

Section: Introductionmentioning

confidence: 99%

Glutamine supplementation improves the efficacy of miltefosine treatment for visceral leishmaniasis

et al. 2020

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BackgroundThe disturbance of host metabolic pathways by Leishmania parasites has crucial consequences for the activation status of immune cells and the outcome of infection. Glutamine has been described as an immunomodulatory amino acid, yet its role during Leishmania infection is still unknown.Visceral leishmaniasis is a life threatening neglected tropical disease affecting around 500,000 and killing 50,000 individuals a year. Despite its obligatory dependence on host cell metabolism and the lack of effective, non-toxic, orally bioavailable anti-leishmanial drugs, Leishmania-perturbed host cell metabolomes and its relation to anti-leishmanial chemotherapy remains unexplored. Transcriptomic analysis performed on L. donovaniinfected macrophages identified patterns of gene expression associated with glutamine metabolism. In vitro and in vivo pharmacological inhibition of glutaminase (GLS), which catalyzes the first reaction in the primary pathway for the catabolism of glutamine, significantly increased the susceptibility to infection demonstrating the role of glutamine metabolism to L. donovani infection. More importantly, we demonstrated that glutamine supplementation during miltefosine treatment potentiates L. donovani clearance through the development of a more effective anti-Leishmania innate and adaptive immune response. Overall, our work demonstrated that glutamine-miltefosine synergy is a novel combined host-and pathogen-directed treatment for combating visceral leishmaniasis.

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Section: Introductionmentioning

confidence: 99%

Glutamine supplementation improves the efficacy of miltefosine treatment for visceral leishmaniasis

et al. 2020

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“…Since the advent of global mass spectrometry methods, metabolomics has proven to be a valuable tool in drug development (46)(47)(48)(49). Recently, metabolomics has provided a greater understanding of Plasmodium parasite metabolite levels and metabolic responses to several common antimalarial drugs (50)(51)(52)(53)(54)(55).…”

mentioning

confidence: 99%

Metabolomic Profiling of the Malaria Box Reveals Antimalarial Target Pathways

Allman

Painter

Jasmeet

et al. 2016

Antimicrob Agents Chemother

130

196

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The threat of widespread drug resistance to frontline antimalarials has renewed the urgency for identifying inexpensive chemotherapeutic compounds that are effective against Plasmodium falciparum, the parasite species responsible for the greatest number of malaria-related deaths worldwide. To aid in the fight against malaria, a recent extensive screening campaign has generated thousands of lead compounds with low micromolar activity against blood stage parasites. A subset of these leads has been compiled by the Medicines for Malaria Venture (MMV) into a collection of structurally diverse compounds known as the MMV Malaria Box. Currently, little is known regarding the activity of these Malaria Box compounds on parasite metabolism during intraerythrocytic development, and a majority of the targets for these drugs have yet to be defined. Here we interrogated the in vitro metabolic effects of 189 drugs (including 169 of the drug-like compounds from the Malaria Box) using ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS). The resulting metabolic fingerprints provide information on the parasite biochemical pathways affected by pharmacologic intervention and offer a critical blueprint for selecting and advancing lead compounds as next-generation antimalarial drugs. Our results reveal several major classes of metabolic disruption, which allow us to predict the mode of action (MoA) for many of the Malaria Box compounds. We anticipate that future combination therapies will be greatly informed by these results, allowing for the selection of appropriate drug combinations that simultaneously target multiple metabolic pathways, with the aim of eliminating malaria and forestalling the expansion of drug-resistant parasites in the field.

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“…Pathogens that persist in the blood as extracellular microbes, such as Trypanosoma brucei, or within red blood cells, such as Plasmodium falciparum, will invariably utilise glucose as the primary carbon source [78]. In these microbes, mitochondrial metabolism is thought to be reduced, altered or absent, although more recent genetic and metabolic profiling approaches have identified additional pathways and alternative carbon sources that promote survival of T. brucei and P. falciparum [79,80].…”

Section: Extracellular Pathogensmentioning

confidence: 99%

Central metabolic interactions of immune cells and microbes: prospects for defeating infections

Traven

Naderer

2019

EMBO Reports

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Antimicrobial drug resistance is threatening to take us to the “pre‐antibiotic era”, where people are dying from preventable and treatable diseases and the risk of hospital‐associated infections compromises the success of surgery and cancer treatments. Development of new antibiotics is slow, and alternative approaches to control infections have emerged based on insights into metabolic pathways in host–microbe interactions. Central carbon metabolism of immune cells is pivotal in mounting an effective response to invading pathogens, not only to meet energy requirements, but to directly activate antimicrobial responses. Microbes are not passive players here—they remodel their metabolism to survive and grow in host environments. Sometimes, microbes might even benefit from the metabolic reprogramming of immune cells, and pathogens such as Candida albicans, Salmonella Typhimurium and Staphylococcus aureus can compete with activated host cells for sugars that are needed for essential metabolic pathways linked to inflammatory processes. Here, we discuss how metabolic interactions between innate immune cells and microbes determine their survival during infection, and ways in which metabolism could be manipulated as a therapeutic strategy.

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Using metabolomics to dissect host–parasite interactions

Cited by 39 publications

References 49 publications

Glutamine supplementation improves the efficacy of miltefosine treatment for visceral leishmaniasis

Glutamine supplementation improves the efficacy of miltefosine treatment for visceral leishmaniasis

Metabolomic Profiling of the Malaria Box Reveals Antimalarial Target Pathways

Central metabolic interactions of immune cells and microbes: prospects for defeating infections

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