Placental Barrier Breakdown Induced by Trypanosoma cruzi-Derived Exovesicles: A Role for MMP-2 and MMP-9 in Congenital Chagas Disease.

Trypanosoma cruzi, the causative agent of Chagas disease, can cross the placental barrier and be transmitted congenitally, yet the mechanisms underlying this process remain incompletely understood. Recent evidence suggests that T. cruzi-derived extracellular vesicles (TcEVs) may facilitate placental invasion by modulating host-pathogen interactions. In this study, we examined the effects of TcEVs on human placental explants (HPEs), focusing on their capacity to disrupt tissue architecture and modulate matrix metalloproteinases MMP-2 and MMP-9, enzymes critical for extracellular matrix remodeling. Term placental chorionic villi were cultured ex vivo and exposed to TcEVs, heat-inactivated TcEVs, infective trypomastigotes, or combinations thereof. TcEVs induced ultrastructural damage, including trophoblast detachment and basal lamina disorganization, which were exacerbated by co-incubation with parasites. Immunohistochemistry and Western blotting revealed significant upregulation of MMP-2 and MMP-9, while gelatin zymography confirmed increased enzymatic activity. Our findings demonstrate that TcEVs independently and synergistically with T. cruzi compromise placental integrity by enhancing MMP expression and activity, thereby priming the placental microenvironment for parasite invasion. Targeting TcEVs signaling or MMP activation may represent a novel strategy to prevent congenital transmission of T. cruzi.