Different genotypes of Trypanosoma cruzi produce distinctive placental environment genetic response in chronic experimental infection

Abstract

Congenital infection of Trypanosoma cruzi allows transmission of this parasite through generations. Despite the problematic that this entails, little is known about the placenta environment genetic response produced against infection. We performed functional genomics by microarray analysis in C57Bl/6J mice comparing placentas from uninfected animals and from animals infected with two different T. cruzi strains: K98, a clone of the non-lethal myotropic CA-I strain (TcI), and VD (TcVI), isolated from a human case of congenital infection. Analysis of networks by GeneMANIA of differentially expressed genes showed that “Secretory Granule” was a pathway down-regulated in both infected groups, whereas “Innate Immune Response” and “Response to Interferon-gamma” were pathways up-regulated in VD infection but not in K98. Applying another approach, the GSEA algorithm that detects small changes in predetermined gene sets, we found that metabolic processes, transcription and macromolecular transport were down-regulated in infected placentas environment and some pathways related to cascade signaling had opposite regulation: over-represented in VD and down-regulated in K98 group. We also have found a stronger tropism to the placental organ by VD strain, by detection of parasite DNA and RNA, suggesting living parasites. Our study is the first one to describe in a murine model the genetic response of placental environment to T. cruzi infection and suggests the development of a strong immune response, parasite genotype-dependent, to the detriment of cellular metabolism, which may contribute to control infection preventing the risk of congenital transmission.

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

“…In addition, ECM components, that are synthetized by the resident cells are also present in tissue and organ samples [ 18 , 19 ]. Similar results have been obtained in animal models, where important changes in murine myocardium metabolic pathways [ 29 ] and in murine placental response [ 24 ] are described. The increase of gene expression of proteases involved in ECM-remodeling (Table 2 ) is in concordance with our previous results showing that the parasite increased expression and activity of matrix metalloproteases (MMP-2 and MMP-9) in human placenta [ 19 ].…”

“…To understand the nature of the interaction between upregulated or downregulated genes, we performed a gene interaction analysis using the GeneMANIA plug-in for Cytoscape 3.0 software [ 24 , 25 ]. For each experimental condition, we analyzed co-expression, co-localization, physical interactions, genetic interactions shared protein domains and pathways amongst all the differentially expressed genes (Fc ≥ 2) in both upregulated or downregulated gene lists.…”

“…Previous studies about transcriptomics related to T. cruzi and Chagas disease have been focused on a single type cell response [ 10 , 28 ] or on tissues or organs in animal models [ 24 , 29 ] but not on human tissues. Here, we describe for the first time, the transcriptomics of an ex vivo human placental tissue model in response to challenges with the parasite.…”

Trypanosoma cruzi Infection at the Maternal-Fetal Interface: Implications of Parasite Load in the Congenital Transmission and Challenges in the Diagnosis of Infected Newborns

“…Another interesting study on the genetic response of the placenta in chronic experimental infections in mice compared the virulence of T. cruzi K98 clone with an isolated parasite from a congenitally infected child (VD/TcVI), and demonstrated that the murine placental infection with the VD isolated parasite was associated with upregulation of genes related to components of the innate immune system and IFN-γ. Even so, no congenital transmission was observed in pups born to infected mice with VD nor K98 parasites (Juiz et al., 2017). The VD/TcVI parasite proved to be more infective in the human trophoblast-derived cell line BeWo compared to the T. cruzi Y strain/TcII (Medina et al., 2018), probably due to a higher virulence and placental tropism, as it was isolated from a human case of congenital infection (Risso et al., 2004).…”

Systematic neonatal screening for congenital Chagas disease in Northeast Brazil: prevalence of Trypanosoma cruzi infection in the Southern region of Sergipe

“…Therefore, the widespread implementation of control measures for other forms of infection, such as congenital transmission, is necessary, and can be defined as a global problem because of its presence in endemic and non-endemic areas 5 . Little attention has been paid to this transmission and although measures have been taken to reduce the number of cases, the genetic response in the placental environment against the infection is not well understood 6 . The congenital transmission is important, especially because it does not limit cases to endemic areas but can also affect non-endemic areas due to the increase in migration, which has become the main transmission route for the disease 7 .…”