Impact of Visceral Leishmaniasis on Local Organ Metabolism in Hamsters

Lesani, Mahbobeh; Gosmanov, Camil; Paun, Andrea; Lewis, Michael D.; McCall, Laura-Isobel

doi:10.3390/metabo12090802

Cited by 7 publications

(5 citation statements)

References 65 publications

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“…The parameters for the spectra and library searches were: 0.02 Da for both precursor ion mass tolerance and MS/MS fragment ion mass tolerance, ≥0.7 cosine score, ≥4 matched peaks, and 100 Da maximum analog search mass difference. All reported annotations, which were collected by an automated script from the GNPS output (https://github.com/camilgosmanov/GNPS) 49 , are within 10 ppm, at Metabolomics Standards Initiative confidence level 2 50 .…”

Section: Lc-ms/ms Data Processingmentioning

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: Lc-ms/ms Data Processingmentioning

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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“…MZmine output files were uploaded and analyzed by Feature-based molecular networking 47 in GNPS for annotation 33 . Annotations were retrieved using a script developed in our laboratory 48 . Lipid annotations such as glycerophosphocholines, glycerophosphoethanolamines and acylcarnitines were further confirmed by searching the LIPID MAPS Structure Database (LMSD and COMPDB) 49,50 .…”

Section: Methodsmentioning

confidence: 99%

Small molecule biomarkers predictive of Chagas disease progression

Liu,

Vucetich,

DeToy

et al. 2024

Preprint

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Chagas disease (CD) is a neglected tropical disease caused by the parasitic protozoan Trypanosoma cruzi. However, only 20% to 30% of infected individuals will progress to severe symptomatic cardiac manifestations. Current treatments are benznidazole and nifurtimox, which are poorly tolerated regimens. Developing a biomarker to determine the likelihood of patient progression would be helpful for doctors to optimize patient treatment strategies. Such a biomarker would also benefit drug discovery efforts and clinical trials. In this study, we combined untargeted and targeted metabolomics to compare serum samples from T. cruzi-infected individuals who progressed to severe cardiac disease, versus infected individuals who remained at the same disease stage (non-progressors). We identified four unannotated biomarker candidates, which were validated in an independent cohort using both untargeted and targeted analysis techniques. Overall, our findings demonstrate that serum small molecules can predict CD progression, offering potential for clinical monitoring.

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“…Feature-based molecular networking (FBMN) was performed using global natural products social molecular networking (GNPS) , based on the parameters in Table . Annotations were generated automatically from the GNPS data using an in-house script ( ). This provides level 2/3 metabolite annotations based on the Metabolomics Standards Initiative rankings .…”

Section: Methodsmentioning

confidence: 99%

Persistent Biofluid Small-Molecule Alterations Induced by Trypanosoma cruzi Infection Are Not Restored by Parasite Elimination

Dean,

Roach,

Ulrich vonBargen

et al. 2023

ACS Infect. Dis.

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Chagas disease (CD), caused by Trypanosoma cruzi (T. cruzi) protozoa, is a complicated parasitic illness with inadequate medical measures for diagnosing infection and monitoring treatment success. To address this gap, we analyzed changes in the metabolome of T. cruzi-infected mice via liquid chromatography tandem mass spectrometry of clinically accessible biofluids: saliva, urine, and plasma. Urine was the most indicative of infection status across mouse and parasite genotypes. Metabolites perturbed by infection in urine include kynurenate, acylcarnitines, and threonylcarbamoyladenosine. Based on these results, we sought to implement urine as a tool for the assessment of CD treatment success. Strikingly, it was found that mice with parasite clearance following benznidazole antiparasitic treatment had an overall urine metabolome comparable to that of mice that failed to clear parasites. These results provide a complementary hypothesis to explain clinical trial data in which benznidazole treatment did not improve patient outcomes in late-stage disease, even in patients with successful parasite clearance. Overall, this study provides insights into new small-molecule-based CD diagnostic methods and a new approach to assess functional responses to treatment.

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Impact of Visceral Leishmaniasis on Local Organ Metabolism in Hamsters

Cited by 7 publications

References 65 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

Small molecule biomarkers predictive of Chagas disease progression

Persistent Biofluid Small-Molecule Alterations Induced by Trypanosoma cruzi Infection Are Not Restored by Parasite Elimination

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