Alterations in Placental Gene Expression of Pregnant Women with Chronic Chagas Disease

Abstract

Trypanosoma cruzi infection in women of reproductive age is associated with congenital transmission and adverse pregnancy outcomes. The placenta is a key barrier to infection. Gene expression profiles of term placental environment from T. cruzi-seropositive (SP) and -seronegative (SN) mothers were characterized by RNA-Seq. Nine pools of placental RNA paired samples were used: three from SN and six from SP tissues. Each pool consisted of female/male newborns and vaginal/cesarean delivery binomials. No newborn was congenitally infected. T. cruzi satellite DNA quantitative PCR in placental tissues and maternal and neonatal blood, and parasite 18S quantitative RT-PCR from placental RNA were negative, except in three SP women's bloodstream. To identify pathways associated with maternal T. cruzi infection, a gene-set association analysis was implemented: SP placental samples showed overexpression of inflammatory response and lymphocytic activation, whereas numerous biosynthetic processes were down-regulated. About 42 genes showed a significant fold-change between SP and SN groups. KISS1 and CGB5 were down-regulated, whereas KIF12, HLA-G, PRG2, TAC3, FN1, and ATXN3L were up-regulated. Several expressed genes in SP placentas encode proteins associated with preeclampsia and miscarriage. This first transcriptomics study in human term placental environment shows a placental response that may affect the fetus while protecting it from parasite infection; this host response could be responsible for the low rate of congenital transmission in chronic Chagas disease.

Host-parasite interaction: changes in human placental gene expression induced by Trypanosoma cruzi

“…Gene set enrichment analysis (GSEA) was performed with GSEA 3.0 software (Broad Institute, Cambridge, Massachussets, USA) [ 21 ]. Each gene set permutation was performed 1000 times, analyses were based on the GO pathways database ( http://geneontology.org /) [ 22 ] and a normalized enrichment score (NES) was obtained for each gene set. An enrichment map from data obtained with GSEA was generated with the Enrichment Map plug-in for Cytoscape 3.0 [ 23 ].…”

“…NES and false discovery rate (FDR) q-value were considered as parameters for the analysis. The NES value allows the comparison of analysis results across gene sets because it considers differences in gene sets sizes corrected by the size of the expression dataset; the FDR represents the estimated probability that a gene set with a given NES represents a false positive finding [ 22 ].…”

PRG2 and AQPEP are misexpressed in fetal membranes in placenta previa and percreta

“…PRG2 (Proteoglycan 2) is expressed in multiple cell types, with its highest expression in the placenta 38 . While the precise role of PRG2 during pregnancy is unknown, PRG2 has been shown to be higher in expression in preeclampsia [39][40][41] , maternal obesity 42 , gestational hypertension 43 , and Chagas disease 44 . PRG2 in its proform is also found at high levels in the placenta 38 and in pregnancy serum 45 , where it forms a complex with PAPPA (pregnancy-associated plasma protein A), a molecule that has been implicated in placental development and pregnancy disorders such as low birth weight 46 , miscarriage 47 , and preeclampsia 48 .…”

Current approaches and developments in transcript profiling of the human placenta

“…Three studies (total n = 53 placentas, 40% affected) have examined the transcriptome of placentas exposed to malaria, Trypanosoma cruzi and infections leading to preterm birth ( Table II: Antenatal infections and inflammation). Expectedly, all affected placentas, regardless of infection type, show dramatic up-regulation of genes involved in the immune and inflammatory response ( Muehlenbachs et al , 2007 ; Ackerman et al , 2016 ; Juiz et al , 2018 ). Better understanding of the functional significance of these transcriptomic alterations may lead to the identification of biomarkers or therapeutic targets for improved clinical management of infections during pregnancy, and reduce infection-induced preterm birth and adverse developmental programming.…”