Placental immunopathology and congenital transmission of Zika virus and Trypanosoma cruzi: comparative mechanisms, immune disturbances, and potential co-infection scenarios

Congenital transmission of Zika virus (ZIKV) and Trypanosoma cruzi ( T. cruzi ) remains a major public health concern in the Americas. Both pathogens cross the placental barrier and cause severe neonatal outcomes, yet no confirmed congenital co-infections have been reported, and their combined effects on maternal–fetal health are unknown. Critical gaps persist regarding placental immunopathology, fetal immune programming, and long-term consequences of prenatal exposure. This review synthesizes current evidence on the routes and mechanisms of placental transmission of ZIKV and T. cruzi , their tropism for placental and fetal tissues, and their distinct immunological footprints. We summarize how congenital infection perturbs fetal immune maturation, including dysregulation of type I/type III interferons, Th1-skewed inflammation, altered immune-tolerance pathways involving HLA-G and PD-1/PD-L1 signaling, and early innate imprinting. We review advances in vaccine development (spanning inactivated, DNA, mRNA, subunit, and viral vector platforms) and highlight barriers such as antibody-dependent enhancement in ZIKV vaccines and the scarcity of pregnancy-relevant preclinical models for T. cruzi . Promising candidates with evidence of fetal or maternal protection in animal studies are described. Therapeutic approaches, including antiviral discovery, immunomodulatory strategies, and emerging anti- T. cruzi compounds are also examined. A detailed understanding of the immunopathology of congenital ZIKV and T. cruzi infections is essential to improve diagnostic accuracy, preventive strategies, and maternal–fetal clinical care. Integrated mechanistic and translational research is urgently needed to assess the plausibility of co-infection, identify biomarkers of fetal risk, and guide the development of pregnancy-safe vaccines and therapeutics, particularly in resource-limited, endemic settings.