Placental transcriptome profiling in congenital Chagas disease: gene networks associated with transmission
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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.
Author summary
Chagas disease, caused by the parasite Trypanosoma cruzi , can be passed from mother to baby during pregnancy, constituting the main transmission way in urban and non-endemic areas. The placenta normally acts as a barrier to protect the fetus, but how this barrier fails in congenitally transmitted cases is still not well understood. Thus, we analyzed the gene expression in placental tissues from three groups: infected mothers that transmitted the parasite, infected mothers that did not transmit it, and uninfected mothers. We found that certain genes involved in immune response, hormone regulation, and the structure of the placenta showed clear differences among these groups. In particular, CGB5 , involved in the production of pregnancy hormones, showed opposite activity patterns depending on whether the mother transmitted the parasite or not. We also found that specific placental cell types that help anchor the placenta or form its protective outer layer changed their expression pattern in transmitting cases. These shifts suggest that both the physical structure and immune system of the placenta may be altered in a way that allows the parasite to reach the fetus. Our findings reveal important molecular clues that could help predict congenital transmission of Chagas disease.
