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

<i>Trypanosoma cruzi</i>, 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 <i>T. cruzi</i>-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 <i>T. cruzi</i> 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 <i>T. cruzi</i>.