Placental transcriptome profiling in congenital Chagas disease: Gene networks associated with transmission

Abstract

Chagas disease, caused by Trypanosoma cruzi, affects over seven million people worldwide. Vertical transmission during pregnancy contributes to the urban spread of the disease, including in non-endemic regions. Although the placenta constitutes a critical barrier against fetal infection, the molecular mechanisms underlying congenital transmission remain poorly understood. To identify placental factors associated with transmission, we performed a transcriptomic analysis of placental tissues from deliveries of congenitally infected (M+B+), exposed but uninfected (M+B−), and unexposed/uninfected (M−B−) newborns. Differential gene expression analysis comparing M+B+ and M−B− placentas revealed overexpression of CEMIP (cell migration–inducing hyaluronidase 1), involved in extracellular matrix (ECM) remodeling and intracellular transport, together with ENSG00000304767, a novel long non-coding RNA located intronically within CEMIP. In contrast, PRRX1 (paired related homeobox 1), CADM3 (cell adhesion molecule 3), and CDH11 (cadherin 11), genes associated with transcriptional regulation and cell–cell adhesion, were underexpressed. In the M+B− versus M−B− comparison, MIR4300HG, a long non-coding RNA hosting MIR4300, was overexpressed, whereas CGB5 (chorionic gonadotropin subunit beta 5), essential for pregnancy maintenance, was underexpressed. Direct comparison between M+B+ and M+B− placentas showed overexpression of the CEMIP-associated lncRNA and CGB5, accompanied by downregulation of CADM3, NEGR1, PDPN, and CDH11, implicating altered adhesion and structural pathways in transmission. Overall, these findings indicate that placental cell adhesion and ECM integrity are disrupted in transmitting placentas. Gene set enrichment analysis using the Gene Ontology library revealed alterations of immune-related pathways in both infected mother groups, while highlighting ECM-related processes—particularly collagen organization and metabolism—as key contributors to transmission events. Cell type enrichment analysis showed overrepresentation of extravillous trophoblasts in M+B+ placentas, with the opposite pattern observed in M+B− cases. Conversely, syncytiotrophoblasts and villous cytotrophoblasts were enriched in non-transmitting placentas relative to controls. Immune-associated placental cell types were consistently reduced in both infected groups. Co-expression network analysis further confirmed compromised placental signaling and structural integrity in transmitting cases, identifying ENPP1 and SLC16A10 as central hub genes. Together, these RNA-seq data define key placental transcriptional alterations associated with congenital T. cruzi transmission which, upon future experimental validation may provide insights into molecular mechanisms governing fetal protection or susceptibility.