Tryp-ing Up Metabolism: Role of Metabolic Adaptations in Kinetoplastid Disease Pathogenesis

Parab, Adwaita R.; McCall, Laura-Isobel

doi:10.1128/iai.00644-20

Cited by 12 publications

(3 citation statements)

References 143 publications

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“…Given the low parasite load during chronic T. cruzi infection, detected metabolites are most likely host-derived. Metabolic changes therefore reflect both direct parasite impacts on host metabolism, as well as host compensatory mechanisms and immunometabolism 60,61 .…”

Section: Discussionmentioning

confidence: 99%

Localized cardiac metabolic trajectories and post-infectious metabolic sequelae in experimental Chagas disease

Liu

Ulrich

Kendricks

et al. 2023

Preprint

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Post-infectious conditions, where clinical symptoms fail to resolve even after pathogen clearance, present major health burdens. However, the mechanisms involved remain poorly understood. In Chagas disease (CD), caused by the parasite Trypanosoma cruzi, antiparasitic agents can clear T. cruzi but late-stage treatment does not improve clinical cardiac outcomes. In this study, we revealed differential metabolic trajectories of cardiac regions during T. cruzi infection, matching sites of clinical symptoms. Incomplete, region-specific, cardiac metabolic restoration was observed in animals treated with the antiparasitic benznidazole, even though parasites were successfully cleared. In contrast, superior metabolic restoration was observed for a combination treatment of reduced-dose benznidazole plus an immunotherapy (Tc24-C4 T. cruzi flagellar protein and TLR4 agonist adjuvant), even though parasite burden reduction was lower. Overall, these results provide a mechanism to explain prior clinical treatment failures in CD and to test novel candidate treatment regimens. More broadly, our results demonstrate a link between persistent metabolic perturbation and post-infectious conditions, with broad implications for our understanding of post-infectious disease sequelae.

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Section: Discussionmentioning

confidence: 99%

Localized cardiac metabolic trajectories and post-infectious metabolic sequelae in experimental Chagas disease

Liu

Ulrich

Kendricks

et al. 2023

Preprint

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“…Previous studies on Trypanosoma cruzi showed elevation of acylcarnitine C20:4 in the esophagus and small intestine during acute-stage infection [7], and likewise we saw elevated acylcarnitines in this study. This may reflect infection-induced alterations in energy metabolism during kinetoplastid infection [48]. Purines and pyrimidines are salvaged by Leishmania.…”

Section: Discussionmentioning

confidence: 99%

Impact of Visceral Leishmaniasis on Local Organ Metabolism in Hamsters

et al. 2022

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Leishmania is an intracellular parasite with different species pathogenic to humans and causing the disease leishmaniasis. Leishmania donovani causes visceral leishmaniasis (VL) that manifests as hepatosplenomegaly, fever, pancytopenia and hypergammaglobulinemia. If left without treatment, VL can cause death, especially in immunocompromised people. Current treatments have often significant adverse effects, and resistance has been reported in some countries. Determining the metabolites perturbed during VL can lead us to find new treatments targeting disease pathogenesis. We therefore compared metabolic perturbation between L. donovani-infected and uninfected hamsters across organs (spleen, liver, and gut). Metabolites were extracted, analyzed by liquid chromatography-mass spectrometry, and processed with MZmine and molecular networking to annotate metabolites. We found few metabolites commonly impacted by infection across all three sites, including glycerophospholipids, ceramides, acylcarnitines, peptides, purines and amino acids. In accordance with VL symptoms and parasite tropism, we found a greater overlap of perturbed metabolites between spleen and liver compared to spleen and gut, or liver and gut. Targeting pathways related to these metabolite families would be the next focus that can lead us to find more effective treatments for VL.

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“…A handful number of drugs are available which are unfortunately associated with toxicity, difficulty in administration, cost or drug resistance. There is a need for novel drugs, and there has been many studies investigating different metabolic pathways in Leishmania that could eventually be exploited for drug development (reviewed in [ 1 – 4 ]).…”

Section: Introductionmentioning

confidence: 99%

Decreased glutamate transport in acivicin resistant Leishmania tarentolae

et al. 2021

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Studies of drug resistance in the protozoan parasites of the genus Leishmania have been helpful in revealing biochemical pathways as potential drug targets. The chlorinated glutamine analogue acivicin has shown good activity against Leishmania cells and was shown to target several enzymes containing amidotransferase domains. We selected a Leishmania tarentolae clone for acivicin resistance. The genome of this resistant strain was sequenced and the gene coding for the amidotransferase domain-containing GMP synthase was found to be amplified. Episomal expression of this gene in wild-type L. tarentolae revealed a modest role in acivicin resistance. The most prominent defect observed in the resistant mutant was reduced uptake of glutamate, and through competition experiments we determined that glutamate and acivicin, but not glutamine, share the same transporter. Several amino acid transporters (AATs) were either deleted or mutated in the resistant cells. Some contributed to the acivicin resistance phenotype although none corresponded to the main glutamate transporter. Through sequence analysis one AAT on chromosome 22 corresponded to the main glutamate transporter. Episomal expression of the gene coding for this transporter in the resistant mutant restored glutamate transport and acivicin susceptibility. Its genetic knockout led to reduced glutamate transport and acivicin resistance. We propose that acivicin binds covalently to this transporter and as such leads to decreased transport of glutamate and acivicin thus leading to acivicin resistance.

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Tryp-ing Up Metabolism: Role of Metabolic Adaptations in Kinetoplastid Disease Pathogenesis

Cited by 12 publications

References 143 publications

Localized cardiac metabolic trajectories and post-infectious metabolic sequelae in experimental Chagas disease

Localized cardiac metabolic trajectories and post-infectious metabolic sequelae in experimental Chagas disease

Impact of Visceral Leishmaniasis on Local Organ Metabolism in Hamsters

Decreased glutamate transport in acivicin resistant Leishmania tarentolae

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