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Zika virus co-opts miRNA networks to persist in placental microenvironments detected by spatial transcriptomics [visium]

ABSTRACT: We and others have demonstrated Zika virus (ZIKV) congenital infection evades double-stranded RNA detection, and may persist in the placenta for the duration of pregnancy without accompanying overt histopathologic inflammation. We used orthogonal approaches to test the hypothesis that ZIKV disrupts placental miRNAs to enable viral persistence and fetal pathogenesis. In primary human trophoblasts, high-throughput sequencing crosslinking and immunoprecipitation (AGO-HITS-CLIP) demonstrated an unexpected disruption of placental miRNA-regulated TGF-β networks. In gnotobiotic mice, absence of microbes rendered normally resistant mice susceptible to congenital ZIKV infection, and placental spatial transcriptomics revealed distinct microenvironments defined by significant upregulation of complement cascade components. Finally, treatment of ZIKV-infected mice with the RNAi-enhancer enoxacin led to loss of ZIKV placental persistence and rescue of fetal growth restriction. These results collectively suggest that ZIKV co-opts miRNA inflammatory regulatory networks to persist in the placenta reservoir, a conduit of vertical transmission and fetal pathogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE205631 | GEO | 2023/06/03

REPOSITORIES: GEO

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Zika virus co-opts miRNA networks to persist in placental microenvironments detected by spatial transcriptomics [AGO-HITS-CLIP]

Project description:We and others have demonstrated Zika virus (ZIKV) congenital infection evades double-stranded RNA detection, and may persist in the placenta for the duration of pregnancy without accompanying overt histopathologic inflammation. We used orthogonal approaches to test the hypothesis that ZIKV disrupts placental miRNAs to enable viral persistence and fetal pathogenesis. In primary human trophoblasts, high-throughput sequencing crosslinking and immunoprecipitation (AGO-HITS-CLIP) demonstrated an unexpected disruption of placental miRNA-regulated TGF-β networks. In gnotobiotic mice, absence of microbes rendered normally resistant mice susceptible to congenital ZIKV infection, and placental spatial transcriptomics revealed distinct microenvironments defined by significant upregulation of complement cascade components. Finally, treatment of ZIKV-infected mice with the RNAi-enhancer enoxacin led to loss of ZIKV placental persistence and rescue of fetal growth restriction. These results collectively suggest that ZIKV co-opts miRNA inflammatory regulatory networks to persist in the placenta reservoir, a conduit of vertical transmission and fetal pathogenesis.

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Zika virus infection induces RNAi-mediated antiviral immunity in human neural progenitors and brain organoids

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Decreased CSTB, RAGE and Axl receptor is associated with Zika infection in the human placenta

Project description:Zika virus (ZIKV) compromises the placental integrity infecting the fetus. However, the mechanisms associated with ZIKV penetration into the placenta leading to fetal infection, are unknown. Cystatin B (CSTB), the receptor for advanced glycation end products (RAGE), and tyrosine-protein kinase receptor UFO (AXL) have been implicated in inflammation. The purpose of this work iis work aims to investigate CSTB, RAGE, and AXL receptor expression in ZIKV infected placental tissues at term. The hypothesis is that in ZIKV-infected placenta, there is overexpression of CSTB and increased inflammation affecting the RAGE and AXL receptor expression. Pathological analyses of 22 placentas were performed to determine changes caused by ZIKV infection. Quantitative proteomics, immunofluorescence, and Western Blot analysis were performed to analyze proteins and pathways affected by ZIKV infection in frozen placenta. Pathological The pathological analysis confirmed decreased size of capillaries, hyperplasia of Hofbauer cells, disruption in the trophoblasts layer, and cell agglutination associated to with ZIKV infection of placental tissue. ZIKV infection was mostly localized to the trophoblast layer. There was a significant decrease in the expression of CSTB, RAGE and AXLCSTB, RAGE and AXL expression in ZIKV positive placenta. This downregulation can impair immune responses and facilitate virus penetration into the placenta. Results are consistent with our previous studies and literature of on ZIKV infection by activation ofng Inflammasome and Pyroptosis through caspase 1 upregulation and affecting the cellular structure, tissue remodeling, and cell differentiation by upregulation of tubulin beta and heat shock protein 27.

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Zika virus co-opts miRNA networks to persist in placental microenvironments detected by spatial transcriptomics

Project description:Zika virus co-opts miRNA networks to persist in placental microenvironments detected by spatial transcriptomics

| PRJNA846741 | ENA

Zika virus co-opts miRNA networks to persist in placental microenvironments detected by spatial transcriptomics [visium]

Project description:Zika virus co-opts miRNA networks to persist in placental microenvironments detected by spatial transcriptomics [visium]

| PRJNA846745 | ENA

Human Cytomegalovirus modifies placental small extracellular vesicle secretion and composition to enhance infection of fetal recipient cells

Project description:Human cytomegalovirus (hCMV) primo-infection, reinfection and/or reactivation is a major issue during pregnancy and affects 1% of live births in western countries, making hCMV the most frequently transmitted virus in utero. Despite the extensive research conducted so far, the pathophysiology of this congenital infection remains unclear. Recently, increasing evidence point out the role of small extracellular vesicles (sEVs) in cell-cell communication underlying the feto-placenta-maternal dialogue during pregnancy. In this study, we examined the impact of hCMV infection on the protein composition and function of placental sEVs. We observed that infection of placental cells led to an alteration of protein composition of their secreted sEVs, suggesting that placental sEVs may acquire a proviral phenotype. Functional studies performed on fetal recipient cells, notably neural stem cells, confirmed the ability of sEVs produced by infected cells to facilitate further infection of naive recipient cells. Altogether, our study demonstrates that placental sEVs are key players of hCMV pathophysiology during congenital infection, and may favor the transmission of the virus towards the fetus.

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