New Metabolic Signature for Chagas Disease Reveals Sex Steroid Perturbation in Humans and Mice

Golizeh, Makan; Nam, John; Chatelain, Eric; Jackson, Yves; Ohlund, Leanne; Rasoolizadeh, Asieh; Camargo, Fabio Vasquez; Mahrouche, Louiza; Fürtös, Alexandra; Sleno, Lekha; Ndao, Momar

doi:10.2139/ssrn.4050413

Cited by 2 publications

(5 citation statements)

References 48 publications

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“…Validation in humans would be desirable, though generating adequately controlled studies with short post-mortem interval to avoid effects on metabolism would be challenging. Our results do however concur with findings in human serum following treatment with the antiparasitic nifurtimox, which likewise showed a lack of metabolic restoration in some patients in positive mode up to three years post-treatment 79 . Longer-term follow-up studies should also be performed, though these are limited by the lifespan of the mouse model.…”

Section: Discussionsupporting

confidence: 90%

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: Discussionsupporting

confidence: 90%

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

Liu

Ulrich

Kendricks

et al. 2023

Preprint

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“…Given prior work showing changes in circulating metabolites with T. cruzi infection in mouse models 29,41 , their association with disease severity in mouse models 30,42 , and infection-associated metabolite changes in human CD patients 28 , we hypothesized that metabolite levels in the serum of T. cruzi -infected individuals could predict CD progression. Overall metabolite profiles between all four groups (infected progressors, infected non-progressors, uninfected progressors and uninfected non-progressors) were very similar.…”

Section: Discussionmentioning

confidence: 99%

“…in human subjects and mouse models 27,28,29 . The level of cardiac acylcarnitines and glycerophosphocholines were correlated with markers of cardiac inflammation and fibrosis 30 .…”

Section: Serum and Urine Metabolites Have Been Identified As Indicato...mentioning

confidence: 99%

“…Serum and urine metabolites have been identified as indicators of T. cruzi infection status in human subjects and mouse models 27,28,29 . The level of cardiac acylcarnitines and glycerophosphocholines were correlated with markers of cardiac inflammation and fibrosis 30 .…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, the cardiac metabolome could be used to predict infection outcome in acute mouse models of infection 31 . A recent study showed that some metabolites could be restored by treatment with the antiparasitic nifurtimox 28 . However, studies of metabolites as biomarkers of CD progression are lacking, especially in humans.…”

Section: Introductionmentioning

confidence: 99%

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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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New Metabolic Signature for Chagas Disease Reveals Sex Steroid Perturbation in Humans and Mice

Cited by 2 publications

References 48 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

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