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

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 plays a key role in preventing fetal infection, although the molecular mechanisms underlying congenital transmission remain unclear. To identify placental factors associated with transmission, we conducted a transcriptomic study comparing placental tissues from deliveries of congenitally infected (M+B+), exposed but uninfected (M+B−), and unexposed/uninfected (M−B−) newborns. Differential gene expression analysis of transmitting placentas revealed that ENSG00000304767, a novel lncRNA sense intronic to CEMIP was overexpressed as well as CGB5, while CEMIP, CADM3, CADH11 and PRXX1 were underexpressed. In non-transmitting placentas, the long non-coding RNA MIR4300 was overexpressed while CGB5 was underexpressed. These results suggest that cell adhesion and the extracellular matrix integrity are altered in transmitting placentas. Additionally, gene set enrichment analysis using the GO library revealed immune-related terms underrepresented in both infected mother groups, and confirmed that extracellular matrix processes, particularly collagen organization and metabolism, constitute important factors in transmission events. Analysis using the Cell Type library showed that extravillous trophoblasts were overrepresented in M+B+, but the opposite in M+B−. In contrast, syncytiotrophoblasts and villous cytotrophoblasts were overrepresented in non-transmitting vs. control cases. Immune-related placental cell types were consistently reduced in both M+ groups when compared to controls. The co-expression network analysis confirmed that the placental signaling and structural integrity were compromised in transmitting cases. ENPP1 and SLC16A10 emerged as hub genes with pivotal roles in the pathways altered during congenital infection. 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.