scholarly journals Congenital Zika syndrome is associated with maternal protein malnutrition

2020 ◽  
Vol 6 (2) ◽  
pp. eaaw6284 ◽  
Author(s):  
J. Barbeito-Andrés ◽  
P. Pezzuto ◽  
L. M. Higa ◽  
A. A. Dias ◽  
J. M. Vasconcelos ◽  
...  
Keyword(s):  
Gene Expression ◽  
Brain Size ◽  
Epidemiological Data ◽  
Protein Malnutrition ◽  
Rna Seq ◽  
Zikv Infection ◽  
Postnatal Brain ◽  
Low Protein ◽  
Congenital Zika Syndrome ◽  
Pregnant Mice

Zika virus (ZIKV) infection during pregnancy is associated with a spectrum of developmental impairments known as congenital Zika syndrome (CZS). The prevalence of this syndrome varies across ZIKV endemic regions, suggesting that its occurrence could depend on cofactors. Here, we evaluate the relevance of protein malnutrition for the emergence of CZS. Epidemiological data from the ZIKV outbreak in the Americas suggest a relationship between undernutrition and cases of microcephaly. To experimentally examine this relationship, we use immunocompetent pregnant mice, which were subjected to protein malnutrition and infected with a Brazilian ZIKV strain. We found that the combination of protein restriction and ZIKV infection leads to severe alterations of placental structure and embryonic body growth, with offspring displaying a reduction in neurogenesis and postnatal brain size. RNA-seq analysis reveals gene expression deregulation required for brain development in infected low-protein progeny. These results suggest that maternal protein malnutrition increases susceptibility to CZS.

scholarly journals Differential gene expression elicited by ZIKV infection in trophoblasts from congenital Zika syndrome discordant twins

2020 ◽  
Vol 14 (8) ◽  
pp. e0008424
Author(s):  
Murilo Sena Amaral ◽  
Ernesto Goulart ◽  
Luiz Carlos Caires-Júnior ◽  
David Abraham Morales-Vicente ◽  
Alessandra Soares-Schanoski ◽  
...  
Keyword(s):  
Gene Expression ◽  
Differential Gene Expression ◽  
Zikv Infection ◽  
Congenital Zika Syndrome ◽  
Differential Gene ◽  
Discordant Twins

scholarly journals Differential gene expression elicited by ZIKV infection in trophoblasts from congenital Zika syndrome discordant twins

2019 ◽  
Author(s):  
Murilo Sena Amaral ◽  
Ernesto Goulart ◽  
Luiz Carlos Caires-Júnior ◽  
David Abraham Morales-Vicente ◽  
Alessandra Soares-Schanoski ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Genetic Background ◽  
Zikv Infection ◽  
Dizygotic Twins ◽  
Susceptibility Factors ◽  
Congenital Zika Syndrome ◽  
Host Genetic ◽  
Discordant Twins

AbstractZika virus (ZIKV) causes congenital Zika syndrome (CZS), which is characterized by fetal demise, microcephaly and other abnormalities. ZIKV in the pregnant woman circulation must cross the placental barrier that includes fetal endothelial cells and trophoblasts, in order to reach the fetus. CZS occurs in ∼1-40% of cases of pregnant women infected by ZIKV, suggesting that mothers’ infection by ZIKV during pregnancy is not deterministic for CZS phenotype in the fetus. Therefore, other susceptibility factors might be involved, including the host genetic background. We have previously shown that in three pairs of dizygotic twins discordant for CZS, neural progenitor cells (NPCs) from the CZS-affected twins presented differential in vitro ZIKV susceptibility compared with NPCs from the non-affected. Here, we analyzed human-induced-pluripotent-stem-cell-derived (hiPSC-derived) trophoblasts from these twins and compared by RNA-Seq the trophoblasts from CZS-affected and non-affected twins. Following in vitro exposure to a Brazilian ZIKV strain (ZIKVBR), trophoblasts from CZS-affected twins were significantly more susceptible to ZIKVBR infection when compared with trophoblasts from the non-affected. Transcriptome profiling revealed no differences in gene expression levels of ZIKV candidate attachment factors, IFN receptors and IFN in the trophoblasts, either before or after ZIKVBR infection. Most importantly, ZIKVBR infection caused, only in the trophoblasts from CZS-affected twins, the downregulation of genes related to extracellular matrix organization and to leukocyte activation, which are important for trophoblast adhesion and immune response activation. In addition, only trophoblasts from non-affected twins secreted significantly increased amounts of chemokines RANTES/CCL5 and IP10 after infection with ZIKVBR. Overall, our results showed that trophoblasts from non-affected twins have the ability to more efficiently activate genes that are known to play important roles in cell adhesion and in triggering the immune response to ZIKV infection in the placenta, and this may contribute to predict protection from ZIKV dissemination into fetuses’ tissues.Author summaryThe Zika virus (ZIKV) infection in adults is usually characterized by mild flu-like symptoms, with most cases remaining asymptomatic. However, in the last years, widespread ZIKV infection was shown for the first time to be associated with congenital Zika syndrome (CZS) and death of neonates. CZS is a very debilitating condition that includes microcephaly and mental retardation, leading to a strong social and health impact. This dramatic condition calls for a careful evaluation of the molecular mechanisms involved in ZIKV infection in the maternal-fetal interface. It is estimated that CZS occurs in ∼1-40% of cases of pregnant women infected by ZIKV, which suggests that different susceptibility factors might be involved, including the host genetic background. By analyzing trophoblast cells that recapitulate the placenta from three pairs of dizygotic twins discordant for CZS, we were able to show that trophoblasts from CZS-affected twins were significantly more susceptible to ZIKV infection when compared with trophoblasts from the non-affected twins. We also provide a detailed picture of genes differentially expressed by trophoblasts from the discordant twins after infection with ZIKV. These genes can be further investigated as possible therapeutic targets to avoid viral dissemination into developing fetus’ tissues.

Maternal diet programs embryonic kidney gene expression

2005 ◽  
Vol 22 (1) ◽  
pp. 48-56 ◽  
Author(s):  
Simon J. M. Welham ◽  
Paul R. Riley ◽  
Angie Wade ◽  
Mike Hubank ◽  
Adrian S. Woolf
Keyword(s):  
Gene Expression ◽  
Maternal Diet ◽  
Epidemiological Data ◽  
Protein Diet ◽  
Low Protein Diet ◽  
Chain Reactions ◽  
Adult Disease ◽  
Polymerase Chain Reactions ◽  
Low Protein ◽  
Blood Pressures

Human epidemiological data associating birth weight with adult disease suggest that organogenesis is “programmed” by maternal diet. In rats, protein restriction in pregnancy produces offspring with fewer renal glomeruli and higher systemic blood pressures than controls. We tested the hypothesis that maternal diet alters gene expression in the metanephros, the precursor of the definitive mammalian kidney. We demonstrated that maternal low-protein diet initiated when pregnancy starts and maintained to embryonic day 13, when the metanephros consists of mesenchyme surrounding a once-branched ureteric bud, is sufficient to significantly reduce glomerular numbers in offspring by about 20%. As assessed by representational difference analyses and real-time quantitative polymerase chain reactions, low-protein diet modulated gene expression in embryonic day 13 metanephroi. In particular, levels of prox-1, the ortholog of Drosophila transcription factor prospero, and cofilin-1, a regulator of the actin cytoskeleton, were reduced. During normal metanephrogenesis, prox-1 protein was first detected in mesenchymal cells around the ureteric tree and thereafter in nascent nephron epithelia, whereas cofilin-1 immunolocalized to bud derivatives and condensing mesenchyme. Previously, we reported that low-protein diets increased mesenchymal apoptosis cells when metanephrogenesis began and thereafter reduced numbers of precursor cells. Collectively, these studies prove that the maternal diet programs the embryonic kidney, altering cell turnover and gene expression at a time when nephrons and glomeruli have yet to form. The human implication is that the maternal diet ingested between conception and 5- 6-wk gestation contributes to the variation in glomerular numbers that are known to occur between healthy and hypertensive populations.

scholarly journals Global RNAseq of ocular cells reveals gene dysregulation in both asymptomatic and with Congenital Zika Syndrome infants exposed prenatally to Zika virus

2020 ◽  
Author(s):  
Livia Rosa-Fernandes ◽  
Amina Bedrat ◽  
Maria Luiza B. dos Santos ◽  
Ana Pinto ◽  
E Lucena ◽  
...  
Keyword(s):  
Gene Expression ◽  
Zika Virus ◽  
Clinical Signs ◽  
Neuronal Cell ◽  
Embryonic Cells ◽  
Zikv Infection ◽  
Gene Dysregulation ◽  
Congenital Zika Syndrome ◽  
Invasive Method ◽  
And Control

AbstractIn 2015, Brazil reported an outbreak identified as Zika virus (ZIKV) infection associated with congenital abnormalities. To date, a total of 86 countries and territories have described evidence of Zika infection and recently the appearance of the African ZIKV lineage in Brazil highlights the risk of a new epidemic. The spectrum of ZIKV infection-induced alterations at both cellular and molecular levels is not completely elucidated. Here, we present for the first time the gene expression responses associated with prenatal ZIKV infection from ocular cells. We applied a recently developed non-invasive method (impression cytology) which use eye cells as a model for ZIKV studies. The ocular profiling revealed significant differences between exposed and control groups, as well as a different pattern in ocular transcripts from Congenital Zika Syndrome (CZS) compared to ZIKV-exposed but asymptomatic infants. Our data showed pathways related to mismatch repair, cancer, and PI3K/AKT/mTOR signaling and genes probably causative or protective in the modulation of ZIKV infection. Ocular cells revealed the effects of ZIKV infection on primordial neuronal cell genes, evidenced by changes in genes associated with embryonic cells. The changes in gene expression support an association with the gestational period of the infection and provide evidence for the resulting clinical and ophthalmological pathologies. Additionally, the findings of cell death- and cancer-associated deregulated genes raise concerns about the early onset of other potential pathologies including the need for tumor surveillance. Our results thus provide direct evidence that infants exposed prenatally to the Zika virus, not only with CZS but also without clinical signs (asymptomatic) express cellular and molecular changes with potential clinical implications.

scholarly journals Postnatal SETD1B is essential for learning and the regulation of neuronal plasticity genes

2021 ◽  
Author(s):  
Alexandra Michurina ◽  
M. Sadman Sakib ◽  
Cemil Kerimoglu ◽  
Dennis Manfred Krueger ◽  
Lalit Kaurani ◽  
...  
Keyword(s):  
Gene Expression ◽  
Neuronal Plasticity ◽  
Memory Function ◽  
Rna Seq ◽  
Set Domain ◽  
Postnatal Brain ◽  
Histone 3 ◽  
Expression Of Genes ◽  
Neuronal Gene ◽  
Learning Impairment

Histone 3 lysine 4 methylation (H3K4me) is mediated by six different lysine methyltransferases. Amongst these enzymes SET domain containing 1b (SETD1B) has been linked to syndromic intellectual disability but its role in the postnatal brain has not been studied yet. Here we employ mice that lack Setd1b from excitatory neurons of the postnatal forebrain and combine neuron-specific ChIP-seq and RNA-seq approaches to elucidate its role in neuronal gene expression. We observe that SETD1B controls the expression of genes with a broad H3K4me3 peak at their promoters that represent neuronal enriched genes linked to learning and memory function. Comparative analysis to corresponding data from conditional Kmt2a and Kmt2b knockout mice suggests that this function is specific to SETD1B. Moreover, postnatal loss of Setd1b leads to severe learning impairment, suggesting that SETD1B-mediated regulation of H3K4me levels in postnatal neurons is critical for cognitive function.

scholarly journals Single-Cell RNA-Seq of Mouse Decidual Leukocytes Reveals Intriguing Gestational Changes in the Immune Cell Landscape and Effects of SRC-1/-2 Double-Deficiency

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A753-A754
Author(s):  
Jingfei Chen ◽  
Jialei Duan ◽  
Alina Montalbano ◽  
Boxun Li ◽  
Gary Hon ◽  
...  
Keyword(s):  
Gene Expression ◽  
Single Cell ◽  
Immune Cell ◽  
Expression Patterns ◽  
Critical Role ◽  
Fetal Lung ◽  
Specific Gene ◽  
Rna Seq ◽  
Cell Clusters ◽  
Pregnant Mice

Abstract Single-cell RNA-seq of Mouse Decidual Leukocytes Reveals Intriguing Gestational Changes in the Immune Cell Landscape and Effects of SRC-1/-2 Double-DeficiencyOur previous findings suggest that the fetus signals the mother when it is ready to be born through secretion of surfactant components/immune modulators, surfactant protein A (SP-A) and platelet-activating factor (PAF) by the fetal lung into amniotic fluid (AF). This occurs with increased proinflammatory cytokine expression by fetal AF macrophages (Mϕ), increased myometrial NF-κB activation and contractile (CAP) gene expression. Steroid receptor coactivator (Src)-1 and Src-2 are critical for developmental induction SP-A and PAF by the fetal lung. The finding that pregnant wild-type (WT) mice carrying Src-1 and Src-2 double-deficient fetuses (Src-1/-2d/d) manifested a marked delay (~38h) in parturition, further suggests that signals for parturition arise from the fetus and that Src-1 and Src-2 serve a critical role. Infiltrating leukocytes at the maternal-fetal interface (MFI)/decidua are known to play a central role in pregnancy maintenance and parturition timing. However, there is limited knowledge regarding gestational changes in immune cell composition toward term. To analyze gestational changes in the composition of immune cells within decidua and effects of Src-1/-2d/d, we conducted single-cell RNA-seq of ~17,000 decidual leukocytes (CD45+) from pregnant mice at 15.5 and 18.5 dpc carrying WT or Src-1/-2d/d fetuses. Unsupervised clustering identified 22 distinct decidual immune cell clusters, comprised of Mϕ, B cells, natural killer cells, neutrophils, dendritic cells and monocytes. Significant differences in cell type composition and transcriptional profiles were found across study groups (WT @ 15.5 dpc vs. 18.5 dpc; Src-1/-2d/dvs. WT @15.5 dpc and 18.5 dpc). Interestingly, in deciduas of pregnant mice carrying WT fetuses, Mϕ and B cell clusters markedly increased between 15.5 and 18.5 dpc, whereas, neutrophils declined; however, these gestational changes did not occur in pregnant mice carrying Src-1/-2d/d fetuses. Differential gene expression and gene ontology enrichment analyses revealed specific gene expression patterns distinguishing these immune cell subtypes to uncover their putative functions. These findings highlight the complexity and dynamics of the decidual immune cell landscape during the transition from myometrial quiescence to contractility, and the fetal-maternal interactions leading to parturition. Support: NIH grants R01-HL050022 (CRM) and P01-HD087150 (CRM), Burroughs Wellcome Preterm Birth Grant #1019823 (CRM).

scholarly journals Exploring miRNAs as the key to understand symptoms induced by ZIKA virus infection through a collaborative database.

2016 ◽  
Author(s):  
Victor Pylro ◽  
Francislon Oliveira ◽  
Daniel Morais ◽  
Sara Orellana ◽  
Fabiano Pais ◽  
...  
Keyword(s):  
Gene Expression ◽  
Zika Virus ◽  
Human Gene ◽  
Noncoding Rnas ◽  
World Health ◽  
Translational Repression ◽  
Zikv Infection ◽  
Small Noncoding Rnas ◽  
Congenital Zika Syndrome ◽  
Health Organization

In early 2015, a ZIKA Virus (ZIKV) infection outbreak was recognized in northeast Brazil, where concerns over its possible links with infant microcephaly have been discussed. Providing a definitive link between ZIKV infection and birth defects is still a big challenge. MicroRNAs (miRNAs), are small noncoding RNAs that regulating post-transcriptional gene expression by translational repression, and play important roles in viral pathogenesis and brain development. The potential for flavivirus-mediated miRNA signaling dysfunction in brain-tissue develop provides a compelling mechanism underlying perceived linked between ZIKV and microcephaly. Here, we provide novel evidences toward to understand the mechanism in which miRNAs can be linked to the congenital ZIKA syndrome symptoms. Moreover, following World Health Organization (WHO) recommendations, we have assembled a database to help target mechanistic investigations of this possible relationship between ZIKV symptoms and miRNA mediated human gene expression, helping to foster potential targets for therapy.

scholarly journals Zika virus infection during development impairs the formation of corpus callosum by disturbing axon guidance and growth of callosal neurons.

2021 ◽  
Author(s):  
Raissa Rilo Christoff ◽  
Jefferson H. Quintanilha ◽  
Raiane O Ferreira ◽  
Jessica C. C. G. Ferreira ◽  
Daniel Menezes Guimaraes ◽  
...  
Keyword(s):  
Corpus Callosum ◽  
Axon Guidance ◽  
Birth Defects ◽  
Zika Virus ◽  
In Utero ◽  
Mouse Embryos ◽  
Rna Seq ◽  
Zikv Infection ◽  
Density Reduction ◽  
Congenital Zika Syndrome

Congenital Zika Syndrome (CZS) is a set of birth defects caused by Zika virus (ZIKV) infection during pregnancy. Microcephaly is its main feature, but other brain abnormalities are found in CZS patients, such as ventriculomegaly, brain calcifications, and dysgenesis of the corpus callosum. Many studies have focused on microcephaly, but it remains unknown how ZIKV infection leads to callosal malformation. To tackle this issue, we infected mouse embryos in utero with Brazilian ZIKV and found that they are born with a reduction in callosal area and density of callosal neurons. ZIKV infection also causes a density reduction of PH3+ cells, intermediate progenitor cells and SATB2+ neurons. Moreover, axonal tracing revealed that callosal axons are reduced and misrouted. Also, ZIKV infected cultures show a reduction of callosal axon length. GFAP labelling showed that in utero infection compromises glial cells responsible for midline axon guidance. The RNA-Seq data from infected brains identified downregulation of axon guidance and axonogenesis related genes. In sum, we showed that ZIKV infection impairs critical steps of corpus callosum formation by disrupting not only neurogenesis but also axon guidance and growth across the midline.

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