Participation of kynurenine pathway metabolites in Trypanosoma cruzi infection of human placenta.

Abstract

Introduction: The kynurenine pathway is a major route of tryptophan (Trp) metabolism, an essential amino acid. This pathway, mediated by Indoleamine 2,3-dioxygenase (IDO), contributes to maternal-fetal tolerance by depletion Trp and generating kynurenines (Kyn). Among the Kyns produced in the placenta, 3-hydroxykynurenine (3-HK) and 3-hydroxy-anthranilic acid (3-HAA) have been shown to affect T. cruzi replication. This study aimed to evaluate the role of kynurenine pathway metabolites in Trypanosoma cruzi (T. cruzi) infection of the human placenta.

Methods: Term human placental explants (n = 8) were infected with 10⁵ T. cruzi trypomastigotes/mL for 24 h. The explants were treated with L-Trp, L-1-methyl-tryptophan (L-1MT), IFN-γ, 3-HK and 3-HAA for 72 or 96 hpi. IDO expression was assessed by immunohistochemistry, and IDO activity was measured in homogenates. L-Kyn concentration was quantified in culture supernatants, while infection levels were determined by qPCR. Statistical analysis included ANOVA with Tukey's post hoc test and Student's t-test (p < 0.05).

Results: L-Trp increased IDO expression and activity, elevating L-Kyn production in both infected and non-infected explants. L-1MT reduced L-Kyn production, whereas IFN-γ stimulated it. Additionally, 3-HK significantly impaired trypomastigotes motility. Both 3-HK and 3-HAA decreased placenta explant infection by T. cruzi.

Conclusion: Metabolites of the kynurenine pathways reduced T. cruzi infection in placental explants, suggesting a potential role in limiting congenital transmission of Chagas disease by modulating parasitic load in human placenta.