Placental miRNA-regulatory networks disrupted by Zika virus (ZIKV) infection

AbstractGut microbiota composition can modulate neuroendocrine function, inflammation, and cellular and immunological responses against different pathogens, including viruses. Zika virus (ZIKV) can infect adult immunocompetent individuals and trigger brain damage and antiviral responses. However, it is not known whether ZIKV infection could impact the gut microbiome from adult immunocompetent mice. Here, we investigated modifications induced by ZIKV infection in the gut microbiome of immunocompetent C57BL/6J mice. Adult C57BL/6J mice were infected with ZIKV and the gut microbiota composition was analyzed by next-generation sequencing of the V4 hypervariable region present in the bacterial 16S rDNA gene. Our data showed that ZIKV infection triggered a significant decrease in the bacteria belonging to Actinobacteria and Firmicutes phyla, and increased Deferribacteres and Spirochaetes phyla components compared to uninfected mice. Interestingly, ZIKV infection triggered a significant increase in the abundance of bacteria from the Spirochaetaceae family in the gut microbiota. Lastly, we demonstrated that modulation of microbiota induced by ZIKV infection may lead to intestinal epithelium damage and intense leukocyte recruitment to the intestinal mucosa. Taken together, our data demonstrate that ZIKV infection can impact the gut microbiota composition and colon tissue homeostasis in adult immunocompetent mice.

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Association between Genetic Variants in NOS2 and TNF Genes with Congenital Zika Syndrome and Severe Microcephaly

Viruses ◽

10.3390/v13020325 ◽

2021 ◽

Vol 13 (2) ◽

pp. 325

Author(s):

Julia A. Gomes ◽

Eduarda Sgarioni ◽

Juliano A. Boquett ◽

Ana Cláudia P. Terças-Trettel ◽

Juliana H. da Silva ◽

...

Keyword(s):

Risk Factors ◽

Zika Virus ◽

Genetic Variants ◽

Educational Level ◽

Congenital Anomalies ◽

Family Income ◽

First Trimester ◽

In Utero ◽

Zikv Infection ◽

Congenital Zika Syndrome

Zika virus (ZIKV) causes Congenital Zika Syndrome (CZS) in individuals exposed prenatally. Here, we investigated polymorphisms in VEGFA, PTGS2, NOS3, TNF, and NOS2 genes as risk factors to CZS. Forty children with CZS and forty-eight children who were in utero exposed to ZIKV infection, but born without congenital anomalies, were evaluated. Children with CZS were predominantly infected by ZIKV in the first trimester (p < 0.001) and had mothers with lower educational level (p < 0.001) and family income (p < 0.001). We found higher risk of CZS due the allele rs2297518[A] of NOS2 (OR = 2.28, CI 95% 1.17–4.50, p = 0.015). T allele and TT/CT genotypes of the TNF rs1799724 and haplotypes associated with higher expression of TNF were more prevalent in children with CZS and severe microcephaly (p = 0.029, p = 0.041 and p = 0.030, respectively). Our findings showed higher risk of CZS due ZIKV infection in the first trimester and suggested that polymorphisms in NOS2 and TNF genes affect the risk of CZS and severe microcephaly.

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Zika Virus Infection Leads to Demyelination and Axonal Injury in Mature CNS Cultures

Viruses ◽

10.3390/v13010091 ◽

2021 ◽

Vol 13 (1) ◽

pp. 91

Author(s):

Verena Schultz ◽

Stephanie L. Cumberworth ◽

Quan Gu ◽

Natasha Johnson ◽

Claire L. Donald ◽

...

Keyword(s):

Nervous System ◽

Neural Development ◽

Zika Virus ◽

Developmental Stages ◽

Cell Types ◽

Neural Cells ◽

Zikv Infection ◽

Axonal Pathology ◽

Time Frames

Understanding how Zika virus (Flaviviridae; ZIKV) affects neural cells is paramount in comprehending pathologies associated with infection. Whilst the effects of ZIKV in neural development are well documented, impact on the adult nervous system remains obscure. Here, we investigated the effects of ZIKV infection in established mature myelinated central nervous system (CNS) cultures. Infection incurred damage to myelinated fibers, with ZIKV-positive cells appearing when myelin damage was first detected as well as axonal pathology, suggesting the latter was a consequence of oligodendroglia infection. Transcriptome analysis revealed host factors that were upregulated during ZIKV infection. One such factor, CCL5, was validated in vitro as inhibiting myelination. Transferred UV-inactivated media from infected cultures did not damage myelin and axons, suggesting that viral replication is necessary to induce the observed effects. These data show that ZIKV infection affects CNS cells even after myelination—which is critical for saltatory conduction and neuronal function—has taken place. Understanding the targets of this virus across developmental stages including the mature CNS, and the subsequent effects of infection of cell types, is necessary to understand effective time frames for therapeutic intervention.

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Analysis of Zika virus capsid-Aedes aegypti mosquito interactome reveals pro-viral host factors critical for establishing infection

Nature Communications ◽

10.1038/s41467-021-22966-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Rommel J. Gestuveo ◽

Jamie Royle ◽

Claire L. Donald ◽

Douglas J. Lamont ◽

Edward C. Hutchinson ◽

...

Keyword(s):

Aedes Aegypti ◽

Protein Interactions ◽

Zika Virus ◽

Label Free ◽

Protein Protein Interactions ◽

Zikv Infection ◽

Ubiquitin Protein Ligase ◽

Mosquito Cells ◽

Endoplasmic Reticulum Protein ◽

Arboviral Diseases

AbstractThe escalating global prevalence of arboviral diseases emphasizes the need to improve our understanding of their biology. Research in this area has been hindered by the lack of molecular tools for studying virus-mosquito interactions. Here, we develop an Aedes aegypti cell line which stably expresses Zika virus (ZIKV) capsid proteins in order to study virus-vector protein-protein interactions through quantitative label-free proteomics. We identify 157 interactors and show that eight have potentially pro-viral activity during ZIKV infection in mosquito cells. Notably, silencing of transitional endoplasmic reticulum protein TER94 prevents ZIKV capsid degradation and significantly reduces viral replication. Similar results are observed if the TER94 ortholog (VCP) functioning is blocked with inhibitors in human cells. In addition, we show that an E3 ubiquitin-protein ligase, UBR5, mediates the interaction between TER94 and ZIKV capsid. Our study demonstrates a pro-viral function for TER94/VCP during ZIKV infection that is conserved between human and mosquito cells.

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Neurodevelopment in Children Exposed to Zika Virus: What Are the Consequences for Children Who Do Not Present with Microcephaly at Birth?

Viruses ◽

10.3390/v13081427 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1427

Author(s):

Paula Sobral da Silva ◽

Sophie Eickmann ◽

Ricardo Ximenes ◽

Celina Martelli ◽

Elizabeth Brickley ◽

...

Keyword(s):

Neurological Examination ◽

Zika Virus ◽

Control Group ◽

P Value ◽

Zikv Infection ◽

Clinical Neurological Examination ◽

Cognitive Delay ◽

Increased Risk ◽

Neurodevelopmental Impairment ◽

The Impact

The relation of Zika virus (ZIKV) with microcephaly is well established. However, knowledge is lacking on later developmental outcomes in children with evidence of maternal ZIKV infection during pregnancy born without microcephaly. The objective of this analysis is to investigate the impact of prenatal exposure to ZIKV on neuropsychomotor development in children without microcephaly. We evaluated 274 children including 235 ZIKV exposed and 39 controls using the Bayley-III Scales of Infant and Toddler Development (BSIDIII) and neurological examination. We observed a difference in cognition with a borderline p-value (p = 0.052): 9.4% of exposed children and none of the unexposed control group had mild to moderate delays. The prevalence of delays in the language and motor domains did not differ significantly between ZIKV-exposed and unexposed children (language: 12.3% versus 12.8%; motor: 4.7% versus 2.6%). Notably, neurological examination results were predictive of neurodevelopmental delays in the BSIDIII assessments for exposed children: 46.7% of children with abnormalities on clinical neurological examination presented with delay in contrast to 17.8% among exposed children without apparent neurological abnormalities (p = 0.001). Overall, our findings suggest that relative to their unexposed peers, ZIKV-exposed children without microcephaly are not at considerably increased risk of neurodevelopmental impairment in the first 42 months of life, although a small group of children demonstrated higher frequencies of cognitive delay. It is important to highlight that in the group of exposed children, an abnormal neuroclinical examination may be a predictor of developmental delay. The article contributes to practical guidance and advances our knowledge about congenital Zika.

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Update on the Transmission of Zika Virus Through Breast Milk and Breastfeeding: A Systematic Review of the Evidence

Viruses ◽

10.3390/v13010123 ◽

2021 ◽

Vol 13 (1) ◽

pp. 123

Author(s):

Elizabeth Centeno-Tablante ◽

Melisa Medina-Rivera ◽

Julia L. Finkelstein ◽

Heather S. Herman ◽

Pura Rayco-Solon ◽

...

Keyword(s):

Breast Milk ◽

Zika Virus ◽

Mother To Child Transmission ◽

Inclusion Criteria ◽

Rt Pcr ◽

Child Transmission ◽

Zikv Infection ◽

Milk Samples ◽

Clinical Complications ◽

Mother To Child

We systematically searched regional and international databases and screened 1658 non-duplicate records describing women with suspected or confirmed ZIKV infection, intending to breastfeed or give breast milk to an infant to examine the potential of mother-to-child transmission of Zika virus (ZIKV) through breast milk or breastfeeding-related practices. Fourteen studies met our inclusion criteria and inform this analysis. These studies reported on 97 mother–children pairs who provided breast milk for ZIKV assessment. Seventeen breast milk samples from different women were found positive for ZIKV via RT-PCR, and ZIKV replication was found in cell cultures from five out of seven breast milk samples from different women. Only three out of six infants who had ZIKV infection were breastfed, no evidence of clinical complications was found to be associated with ZIKV RNA in breast milk. This review updates our previous report by including 12 new articles, in which we found no evidence of ZIKV mother-to-child transmission through breast milk intake or breastfeeding. As the certainty of the present evidence is low, additional studies are still warranted to determine if ZIKV can be transmitted through breastfeeding.

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Risk of sexually transmitted Zika virus in a cohort of economically disadvantaged urban residents

The Journal of Infectious Diseases ◽

10.1093/infdis/jiab001 ◽

2021 ◽

Author(s):

Juan P Aguilar Ticona ◽

Huma Baig ◽

Nivison Nery Jr. ◽

Simon Doss-Gollin ◽

Gielson A Sacramento ◽

...

Keyword(s):

Sexual Behavior ◽

Sexually Transmitted Infections ◽

Zika Virus ◽

Disease Burden ◽

Urban Community ◽

Urban Residents ◽

Zikv Infection ◽

Retrospective Survey ◽

Sexually Transmitted ◽

Increased Risk

Abstract In order to understand the disease burden of sexually transmitted Zika virus (ZIKV), we prospectively followed a cohort of 359 adult and adolescent residents of an urban community in Salvador, Brazil through the 2015 ZIKV epidemic. Later, in 2017, we used a retrospective survey to associate sexual behavior during the epidemic with ZIKV infection as defined by IgG3-NS1 ELISA. We found that males who engaged in casual sexual encounters during the epidemic were more likely (ORa=6.2; 95%CI 1.2–64.1) to be ZIKV positive, suggesting that specific groups may be at increased risk of sexually transmitted infections.

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Evaluation of ELISA-Based Multiplex Peptides for the Detection of Human Serum Antibodies Induced by Zika Virus Infection across Various Countries

Viruses ◽

10.3390/v13071319 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1319

Author(s):

Maria del Pilar Martinez Viedma ◽

Stephen Panossian ◽

Kennedy Gifford ◽

Kimberly García ◽

Isis Figueroa ◽

...

Keyword(s):

Zika Virus ◽

Clinical Symptoms ◽

Sampling Period ◽

Public Health Issue ◽

Diagnostic Challenge ◽

Zikv Infection ◽

Past Infection ◽

Neurological Sequelae ◽

Methods Development ◽

Specificity And Sensitivity

Zika virus (ZIKV) is a mosquito-borne Flavivirus with a positive-sense RNA genome, which are generally transmitted through the bite of an infected Aedes mosquito. ZIKV infections could be associated with neurological sequelae that, and otherwise produces similar clinical symptoms as other co-circulating pathogens. Past infection with one member of the Flavivirus genus often induces cross-reactive antibodies against other flaviruses. These attributes complicate the ability to differentially diagnose ZIKV infection from other endemic mosquito-borne viruses, making it both a public health issue as well as a diagnostic challenge. We report the results from serological analyses using arbovirus-specific peptides on 339 samples that were previously collected from 6 countries. Overall, we found that our multiplexed peptide-based ELISA was highly efficient for identifying ZIKV antibodies as early as 2 weeks post infection, and that it correlates with microneutralization, plaque reduction neutralization tests (PRNTs) and commercial tests for ZIKV in previously characterized samples. We observed that seropositivity varied by patient cohort, reflecting the sampling period in relation to the 2015–2016 ZIKV outbreak. This work evaluates the accuracy, specificity, and sensitivity of our peptide-based ELISA method for detecting ZIKV antibodies from geographically diverse regions. These findings can contribute to ongoing serological methods development and can be adapted for use in future studies.

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Palmitoleate Protects against Zika Virus-Induced Placental Trophoblast Apoptosis

Biomedicines ◽

10.3390/biomedicines9060643 ◽

2021 ◽

Vol 9 (6) ◽

pp. 643

Author(s):

Philma Glora Muthuraj ◽

Aryamav Pattnaik ◽

Prakash K. Sahoo ◽

Md Torikul Islam ◽

Asit K. Pattnaik ◽

...

Keyword(s):

Fatty Acid ◽

Er Stress ◽

Zika Virus ◽

Intrauterine Growth Restriction ◽

Maternal Circulation ◽

Zikv Infection ◽

Human Trophoblast ◽

Homologous Protein ◽

Stress Markers ◽

Infected Cells

Zika virus (ZIKV) infection in pregnancy is associated with the development of microcephaly, intrauterine growth restriction, and ocular damage in the fetus. ZIKV infection of the placenta plays a crucial role in the vertical transmission from the maternal circulation to the fetus. Our previous study suggested that ZIKV induces endoplasmic reticulum (ER) stress and apoptosis of placental trophoblasts. Here, we showed that palmitoleate, an omega-7 monounsaturated fatty acid, prevents ZIKV-induced ER stress and apoptosis in placental trophoblasts. Human trophoblast cell lines (JEG-3 and JAR) and normal immortalized trophoblasts (HTR-8) were used. We observed that ZIKV infection of the trophoblasts resulted in apoptosis and treatment of palmitoleate to ZIKV-infected cells significantly prevented apoptosis. However, palmitate (saturated fatty acid) did not offer protection from ZIKV-induced ER stress and apoptosis. We also observed that the Zika viral RNA copies were decreased, and the cell viability improved in ZIKV-infected cells treated with palmitoleate as compared to the infected cells without palmitoleate treatment. Further, palmitoleate was shown to protect against ZIKV-induced upregulation of ER stress markers, C/EBP homologous protein and X-box binding protein-1 splicing in placental trophoblasts. In conclusion, our studies suggest that palmitoleate protects placental trophoblasts against ZIKV-induced ER stress and apoptosis.

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Clinical Regimens of Favipiravir Inhibit Zika Virus Replication in the Hollow-Fiber Infection Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00967-18 ◽

2018 ◽

Vol 62 (9) ◽

Cited By ~ 5

Author(s):

Camilly P. Pires de Mello ◽

Xun Tao ◽

Tae Hwan Kim ◽

Michael Vicchiarelli ◽

Jürgen B. Bulitta ◽

...

Keyword(s):

Hollow Fiber ◽

Zika Virus ◽

Human Cell Line ◽

Infection Model ◽

Zikv Infection ◽

Dosage Regimens ◽

Viral Burden ◽

Human Pharmacokinetic ◽

Dose Dependent Fashion ◽

Spectrum Activity

ABSTRACT Zika virus (ZIKV) infection is associated with serious, long-term neurological manifestations. There are currently no approved therapies for the treatment or prevention of ZIKV infection. Favipiravir (FAV) is a viral polymerase inhibitor with broad-spectrum activity. Our prior studies used static FAV concentrations and demonstrated promising activity. However, the anti-ZIKV activity of dynamic FAV concentrations has never been evaluated in a human cell line. Here we employed the hollow-fiber infection model (HFIM) to simulate the human pharmacokinetic (PK) profiles associated with the clinically utilized FAV dosage regimens against influenza and Ebola viruses and assessed the viral burden profiles. Clinically achievable FAV concentrations inhibited ZIKV replication in HUH-7 cells in a dose-dependent fashion (50% effective concentration = 236.5 μM). The viral burden profiles under dynamic FAV concentrations were predicted by use of a mechanism-based mathematical model (MBM) and subsequently successfully validated in the HFIM. This validated, translational MBM can now be used to predict the anti-ZIKV activity of other FAV dosage regimens in the presence of between-patient variability in pharmacokinetics. This approach can be extended to rationally optimize FAV combination dosage regimens which hold promise to treat ZIKV infections in nonpregnant patients.

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