Animal Models of Trypanosoma cruzi Congenital Transmission

Avalos-Borges, Eduardo E.; Rios, Lizette E.; Jiménez‐Coello, Matilde; Ortega-Pacheco, Antonio; Garg, Nisha

doi:10.3390/pathogens11101172

Cited by 5 publications

(7 citation statements)

References 109 publications

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“…However, in both cases, the hemochorial placenta enables direct contact between fetal trophoblast cells and maternal blood 34 . The notable difference in placental villous structure between mice and humans is related to maternal-fetal exchange and endocrine functions 36 . Among the various similarities and differences in anatomy and histology between human and mouse placentas, mice offer a valuable model for comprehending the impact of various stimuli on pregnancy outcomes.…”

Section: Discussionmentioning

confidence: 99%

Subunit nanovaccine elicited T cell functional activation controls Trypanosoma cruzi mediated maternal and placental tissue damage and improves pregnancy outcomes in mice

Rios,

Lokugamage,

Choudhuri

et al. 2023

npj Vaccines

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This study investigated a candidate vaccine effect against maternal Trypanosoma cruzi (Tc) infection and improved pregnancy outcomes. For this, TcG2 and TcG4 were cloned in a nanoplasmid optimized for delivery, antigen expression, and regulatory compliance (nano2/4 vaccine). Female C57BL/6 mice were immunized with nano2/4, infected (Tc SylvioX10), and mated 7-days post-infection to enable fetal development during the maternal acute parasitemia phase. Females were euthanized at E12–E17 (gestation) days. Splenic and placental T-cell responses were monitored by flow cytometry. Maternal and placental/fetal tissues were examined for parasites by qPCR and inflammatory infiltrate by histology. Controls included age/immunization-matched non-pregnant females. Nano2/4 exhibited no toxicity and elicited protective IgG2a/IgG1 response in mice. Nano2/4 signaled a splenic expansion of functionally active CD4+ effector/effector memory (Tem) and central memory (Tcm) cells in pregnant mice. Upon challenge infection, nano2/4 increased the splenic CD4+ and CD8+T cells in all mice and increased the proliferation of CD4+Tem, CD4+Tcm, and CD8+Tcm subsets producing IFNγ and cytolytic molecules (PRF1, GZB) in pregnant mice. A balanced serum cytokines/chemokines response and placental immune characteristics indicated that pregnancy prevented the overwhelming damaging immune response in mice. Importantly, pregnancy itself resulted in a significant reduction of parasites in maternal and fetal tissues. Nano2/4 was effective in arresting the Tc-induced tissue inflammatory infiltrate, necrosis, and fibrosis in maternal and placental tissues and improving maternal fertility, placental efficiency, and fetal survival. In conclusion, we show that maternal nano2/4 vaccination is beneficial in controlling the adverse effects of Tc infection on maternal health, fetal survival, and pregnancy outcomes.

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Section: Discussionmentioning

confidence: 99%

Subunit nanovaccine elicited T cell functional activation controls Trypanosoma cruzi mediated maternal and placental tissue damage and improves pregnancy outcomes in mice

Rios,

Lokugamage,

Choudhuri

et al. 2023

npj Vaccines

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“…Other investigators have found parasitic lesions in placental tissues at the marginal zone ( Fernandez-Aguilar et al, 2005 ). These observations suggest that T. cruzi may reach umbilical and fetal capillaries either by infecting SYNs or through invasion of the marginal sinus epithelial cells ( Carlier et al, 2020 ; Avalos-Borges et al, 2022 ).…”

Section: Introductionmentioning

confidence: 95%

“…The main mechanisms and immunoregulatory factors that modulate T. cruzi fetal infection have yet to be determined. Several animal and ex vivo models have been used to study CD congenital transmission ( Avalos-Borges et al, 2022 ). For instance, modulation of the NF-κB and Toll-like receptors (TLRs) pathways, as well as the role of the placental barrier integrity in parasite infection have been evaluated in chorionic villi explants ( Diaz-Lujan et al, 2016 ; Liempi et al, 2016 ; Castillo et al, 2017a , b ) and cord blood cells ( Ait Djebbara et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

The transcriptome landscape of 3D-cultured placental trophoblasts reveals activation of TLR2 and TLR3/7 in response to low Trypanosoma cruzi parasite exposure

Silberstein,

Chung,

Debrabant

2023

Front. Microbiol.

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Vertical transmission of Trypanosoma cruzi (T. cruzi) become a globalized health problem accounting for 22% of new cases of Chagas disease (CD). Congenital infection is now considered the main route of CD spread in non-endemic countries where no routine disease testing of pregnant women is implemented. The main mechanisms that lead to fetal infection by T. cruzi remain poorly understood. Mother-to-child transmission may occur when bloodstream trypomastigotes interact with the syncytiotrophoblasts (SYNs) that cover the placenta chorionic villi. These highly specialized cells function as a physical barrier and modulate immune responses against pathogen infections. To model the human placenta environment, we have previously used a three-dimensional (3D) cell culture system of SYNs that exhibits differentiation characteristics comparable to placental trophoblasts. Further, we have shown that 3D-grown SYNs are highly resistant to T. cruzi infection. In this work, we used RNA sequencing and whole transcriptome analysis to explore the immunological signatures that drive SYNs’ infection control. We found that the largest category of differentially expressed genes (DEGs) are associated with inflammation and innate immunity functions. Quantitative RT-PCR evaluation of selected DEGs, together with detection of cytokines and chemokines in SYNs culture supernatants, confirmed the transcriptome data. Several genes implicated in the Toll-like receptors signaling pathways were upregulated in 3D-grown SYNs. In fact, TLR2 blockade and TLR3/7 knockdown stimulated T. cruzi growth, suggesting that these molecules play a significant role in the host cell response to infection. Ingenuity Pathway Analysis of DEGs predicted the activation of canonical pathways such as S100 protein family, pathogen induced cytokine storm, wound healing, HIF1α signaling and phagosome formation after T. cruzi exposure. Our findings indicate that SYNs resist infection by eliciting a constitutive pro-inflammatory response and modulating multiple defense mechanisms that interfere with the parasite’s intracellular life cycle, contributing to parasite killing and infection control.

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“…15 It has been shown that the activity of nitric oxide is a key factor for limiting placental infection, 16,17 and it is well established that the expression of nitric oxide is stimulated by pro-inflammatory cytokines. 7,18 However, little is known about the source of the cytokines found in the sera of the pregnant women with Chagas, or about the immunological response of the specific placental cells. In addition, there is little knowledge available concerning the expression of cytokines and their role during the first contact between placental barrier structures and T. cruzi during the phase of invasion and multiplication of the parasite within the placental chorionic villous.…”

Section: Introductionmentioning

confidence: 99%

“…It has been shown that the activity of nitric oxide is a key factor for limiting placental infection, 16,17 and it is well established that the expression of nitric oxide is stimulated by pro‐inflammatory cytokines 7,18 . However, little is known about the source of the cytokines found in the sera of the pregnant women with Chagas, or about the immunological response of the specific placental cells.…”

Section: Introductionmentioning

confidence: 99%

Pro‐inflammatory cytokines are modified during the multiplication of Trypanosoma cruzi within the placental chorionic villi and are associated with the level of infection via the signaling pathway NF‐κB

Benizio,

Moreira‐Espinoza,

Triquell

et al. 2023

American J Rep Immunol

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ProblemCongenital Trypanosoma cruzi (T. cruzi) infection has been associated with changes in the levels of TNF‐α and IFN‐γ during the pregnancy. Therefore, we propose to study the participation and dynamics of proinflammatory cytokines in the infection process of placental explants infected by T. cruzi in vitro.Method of StudyChorionic villous explants (CVE) obtained of human term placentas (n = 8) from normal pregnancies were cultured with 105 trypomastigotes/mL of Tulahuen strain DTU VI for 0, 2, 4, 16, 24, 48 and 72 h. Explants were treated with sulfasalazine (SULF) (5 mM) and N‐acetyl‐cysteine (NAC) (15 mM), as inhibitors molecules of NF‐κB pathway, or LPS (1 μg/mL) for 24 and 72 h p.i. Motile trypomastigotes were counted in culture supernatants. Immunohistochemistry and ELISA for TNF‐α, IFN‐γ, IL‐1β, IL‐4, and IL‐10 were performed in CVE and culture supernatants respectively. The parasite load was measured by RT‐qPCR.ResultsT. cruzi invades the chorionic villi from 4 h p.i. increasing significantly its DNA at 48 and 72 h p.i. of culture (parasite multiplication phase). They were detected in stromal cells, which was related to elevation of TNF‐α, IL‐1β, IFN‐γ, and IL‐10. The inhibition of NF‐κB activity in the explants decreased the production of the analyzed cytokines, showing elevated levels of T. cruzi DNA during the multiplication phase of the parasite.ConclusionsPlacental tissue modifies the secretion of pro‐inflammatory cytokines during the phase of parasite multiplication, but not during the invasion phase, which in turns modifies the level of infection via the signaling pathway NF‐κB.

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Animal Models of Trypanosoma cruzi Congenital Transmission

Cited by 5 publications

References 109 publications

Subunit nanovaccine elicited T cell functional activation controls Trypanosoma cruzi mediated maternal and placental tissue damage and improves pregnancy outcomes in mice

Subunit nanovaccine elicited T cell functional activation controls Trypanosoma cruzi mediated maternal and placental tissue damage and improves pregnancy outcomes in mice

The transcriptome landscape of 3D-cultured placental trophoblasts reveals activation of TLR2 and TLR3/7 in response to low Trypanosoma cruzi parasite exposure

Pro‐inflammatory cytokines are modified during the multiplication of Trypanosoma cruzi within the placental chorionic villi and are associated with the level of infection via the signaling pathway NF‐κB

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