Unraveling Placental Gene Expression: Transcriptomics Networks Comparing Infected and Non-Infected Births from Women with Chagas Disease

Chagas disease, caused by Trypanosoma cruzi, affects over seven million people globally. Vertical transmission during pregnancy significantly contributes to the urban spread of the disease, even in non-endemic areas. The placental barrier is key to preventing fetal infection, yet the molecular mechanisms underlying congenital transmission remain unclear. To identify placental factors associated with transmission, we conducted a transcriptomic analysis comparing placental tissues from deliveries of congenitally infected (M+B+), exposed but uninfected (M+B-), and unexposed/uninfected (M-B-) newborns.Differential gene expression (DEG) analysis revealed that ENSG00000304767, a novel lncRNA sense intronic to CEMIP, was overexpressed, and CADM3 and CADH11 underexpressed in M+B+ versus both control groups. CEMIP and PRXX1 were notably dysregulated between M+B+ and M-B-, while MIR4300 and CGB5 differed between M+B- and M-B-. CGB5, encoding chorionic gonadotropin beta subunit 5, was upregulated in M+B+ versus M+B-, but downregulated in M+B- versus M-B-, indicating potential involvement in transmission mechanisms.Gene set enrichment analysis using the GO library revealed underrepresentation of several immune-related terms in both infected mother groups. Extracellular matrix processes, particularly collagen organization and metabolism, appeared to be key differences in occurrence of transmission. Analysis using the Cell Type library showed overrepresentation of extravillous trophoblasts in M+B+, while these were underrepresented in M+B-. Syncytiotrophoblasts and villous cytotrophoblasts were underrepresented in M+B+ versus M+B- but overrepresented in M+B- versus M-B-. Immune-related placental cell types were reduced in both M+ groups compared to unexposed controls.Co-expression network analysis identified a module negatively correlated with M+B+, enriched in genes downregulated in this group. Functional analysis revealed enrichment in extracellular matrix organization, glycosaminoglycan binding, and growth factor interaction pathways, suggesting compromised placental structural integrity and signaling in transmitting cases. Noteworthy, two hub genes, ENPP1 and SLC16A10, were identified as central nodes within this module.These findings highlight key placental transcriptional alterations linked to congenital T. cruzi transmission and provide insight into potential molecular mechanisms of fetal protection or susceptibility.