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:10.1016/j.heliyon.2022.e12380

Cited by 8 publications

(5 citation statements)

References 60 publications

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“…It is possible that metabolism gradually improves over time though incomplete metabolic restoration was also observed in heart tissue 56 days posttreatment . A study of CD patients treated with the other antiparasitic nifurtimox showed restoration of many but not all metabolic perturbations up to three years after treatment . In contrast, the BENEFIT trial that followed patients 7 years posttreatment did not observe improved clinical outcomes in benznidazole-treated patients, indicating that longer follow up may not show improvements and that our urine metabolome analysis could be well reflective of clinical outcomes.…”

Section: Discussionmentioning

confidence: 82%

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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Section: Discussionmentioning

confidence: 82%

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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show abstract

“…It is possible that metabolism gradually improves over time, though incomplete metabolic restoration was also observed in heart tissue 56 days post-treatment 47 . A study of CD patients treated with the other antiparasitic nifurtimox showed restoration of many but not all metabolic perturbations up to three years after treatment 49 . In contrast, the BENEFIT trial that followed patients 7 years post-treatment did not observe any improved clinical outcomes in benznidazole-treated patients 7 , indicating that longer follow up may not show improvements and that our urine metabolome analysis may be well reflective of clinical outcomes.…”

Section: Discussionmentioning

confidence: 99%

Persistent biofluid small molecule alterations induced byTrypanosoma cruziinfection are not restored by antiparasitic treatment

Dean

Roach

vonBargen

et al. 2023

Preprint

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Chagas Disease (CD), caused byTrypanosoma 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 ofT. cruzi-infected mice via liquid chromatography tandem mass spectrometry analysis 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 the urine include kynurenate, acylcarnitines, and threonylcarbamoyladenosine. Based on these results, we sought to implement urine as a tool for assessment of CD treatment success. Strikingly, it was found that mice with parasite clearance following benznidazole antiparasitic treatment had comparable overall urine metabolome to mice that failed to clear parasites. These results match with clinical trial data in which benznidazole treatment did not improve patient outcomes in late-stage disease. Overall, this study provides insights into new small molecule-based CD diagnostic methods and a new approach to assess functional treatment response.

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“…Indeed, reduced levels of purines have been observed in mouse models and in human systems [72][73][74], along with many other nutrients essential to T. cruzi: vitamins B2, B6, and B12, lysine, valine, arginine, and phenylalanine [74], though with some conflicting results between studies [72]. A caveat is that reduced levels of these nutrients cannot automatically be interpreted as direct uptake by the parasite, given the low parasite burden during chronic infection and the observation that some of these changes persist even after antiparasitic treatment, such as partial purine depletion [73,75].…”

Section: Host Metabolic Changes: Protective or Maladaptive?mentioning

confidence: 99%

“…While the goal of current CD treatments is to clear the parasite, this is insufficient to fully restore infection-associated metabolic alterations [73,75,170,171]. Metabolic modulators are uniquely poised to address these changes, renormalize metabolism, and improve disease symptoms (Table 2).…”

Section: Immune Modulation Through Metabolism To Improve Chagas Disea...mentioning

confidence: 99%

Small molecule mediators of host-T. cruzi-environment interactions in Chagas disease

Kwakye-Nuako,

Middleton,

McCall

2024

PLoS Pathog

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Small molecules (less than 1,500 Da) include major biological signals that mediate host-pathogen-microbiome communication. They also include key intermediates of metabolism and critical cellular building blocks. Pathogens present with unique nutritional needs that restrict pathogen colonization or promote tissue damage. In parallel, parts of host metabolism are responsive to immune signaling and regulated by immune cascades. These interactions can trigger both adaptive and maladaptive metabolic changes in the host, with microbiome-derived signals also contributing to disease progression. In turn, targeting pathogen metabolic needs or maladaptive host metabolic changes is an important strategy to develop new treatments for infectious diseases. Trypanosoma cruzi is a single-celled eukaryotic pathogen and the causative agent of Chagas disease, a neglected tropical disease associated with cardiac and intestinal dysfunction. Here, we discuss the role of small molecules during T. cruzi infection in its vector and in the mammalian host. We integrate these findings to build a theoretical interpretation of how maladaptive metabolic changes drive Chagas disease and extrapolate on how these findings can guide drug development.

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New metabolic signature for Chagas disease reveals sex steroid perturbation in humans and mice

Cited by 8 publications

References 60 publications

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

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

Persistent biofluid small molecule alterations induced byTrypanosoma cruziinfection are not restored by antiparasitic treatment

Small molecule mediators of host-T. cruzi-environment interactions in Chagas disease

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