Zika viruses of both African and Asian lineages cause fetal harm in a vertical transmission model

AbstractCongenital Zika virus (ZIKV) infection was first linked to birth defects during the American outbreak 1–3. It has been proposed that mutations unique to the Asian/American-genotype explain, at least in part, the ability of Asian/American ZIKV to cause congenital Zika syndrome (CZS) 4,5. Recent studies identified mutations in ZIKV infecting humans that arose coincident with the outbreak in French Polynesia and were stably maintained during subsequent spread to the Americas 5. Here we show that African ZIKV can infect and harm fetuses and that the S139N mutation that has been associated with the American outbreak is not essential for fetal harm. Our findings, in a vertical transmission mouse model, suggest that ZIKV will remain a threat to pregnant women for the foreseeable future, including in Africa, southeast Asia, and the Americas. Additional research is needed to better understand the risks associated with ZIKV infection during pregnancy, both in areas where the virus is newly endemic and where it has been circulating for decades.

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Risk estimates for microcephaly related to Zika virus infection - from French Polynesia to Bahia, Brazil

10.1101/051060 ◽

2016 ◽

Cited By ~ 3

Author(s):

Michael A Johansson ◽

Luis Mier-y-Teran-Romero ◽

Jennita Reefhuis ◽

Suzanne M Gilboa ◽

Susan L Hills

Keyword(s):

Virus Infection ◽

Confidence Interval ◽

Infection Rate ◽

Birth Defects ◽

Zika Virus ◽

First Trimester ◽

French Polynesia ◽

Zikv Infection ◽

Risk Estimates ◽

First Trimester Of Pregnancy

Zika virus (ZIKV) infection during pregnancy has been linked to birth defects,1 yet the magnitude of risk remains uncertain. A study of the Zika outbreak in French Polynesia estimated that the risk of microcephaly due to ZIKV infection in the first trimester of pregnancy was 0.95% (95% confidence interval: 0.34-1.91%), based on eight microcephaly cases identified retrospectively in a population of approximately 270,000 people with an estimated 66% ZIKV infection rate.2

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

10.1101/2021.11.11.468315 ◽

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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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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Asymptomatic Prenatal Zika Virus Infection and Congenital Zika Syndrome

Open Forum Infectious Diseases ◽

10.1093/ofid/ofy073 ◽

2018 ◽

Vol 5 (4) ◽

Cited By ~ 17

Author(s):

Enny S Paixao ◽

Wei-Yee Leong ◽

Laura C Rodrigues ◽

Annelies Wilder-Smith

Keyword(s):

Virus Infection ◽

Birth Defects ◽

Prospective Studies ◽

Zika Virus ◽

Retrospective Studies ◽

Recall Bias ◽

Virus Infections ◽

Fetal Outcomes ◽

Zika Virus Infection ◽

Congenital Zika Syndrome

Abstract To investigate to what extent asymptomatic vs symptomatic prenatal Zika virus infections contribute to birth defects, we identified 3 prospective and 8 retrospective studies. The ratio varied greatly in the retrospective studies, most likely due to recruitment and recall bias. The prospective studies revealed a ratio of 1:1 for asymptomatic vs symptomatic maternal Zika infections resulting in adverse fetal outcomes.

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Zika Virus Pathogenesis: From Early Case Reports to Epidemics

Viruses ◽

10.3390/v11100886 ◽

2019 ◽

Vol 11 (10) ◽

pp. 886 ◽

Cited By ~ 5

Author(s):

Ryan D. Pardy ◽

Martin J. Richer

Keyword(s):

Risk Factors ◽

Zika Virus ◽

Case Reports ◽

Viral Persistence ◽

The Body ◽

Therapeutic Approaches ◽

Zikv Infection ◽

Congenital Zika Syndrome ◽

Early Case ◽

The Impact

For the first 60 years following its isolation, Zika virus (ZIKV) remained a relatively poorly described member of the Flaviviridae family. However, since 2007, it has caused a series of increasingly severe outbreaks and is now associated with neurological symptoms such as Guillain-Barré syndrome and congenital Zika syndrome (CZS). A number of reports have improved our understanding of rare complications that may be associated with ZIKV infection in adults, the areas of the body to which it spreads, and viral persistence in various tissues. Likewise, studies on the effect of ZIKV infection during pregnancy have identified risk factors for CZS and the impact this syndrome has on early childhood. Understanding these outcomes and the factors that drive ZIKV pathogenesis are key to developing vaccination and therapeutic approaches to avoid these severe and potentially debilitating symptoms.

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Zika Virus-Immune Plasmas from Symptomatic and Asymptomatic Individuals Enhance Zika Pathogenesis in Adult and Pregnant Mice

mBio ◽

10.1128/mbio.00758-19 ◽

2019 ◽

Vol 10 (4) ◽

Cited By ~ 13

Author(s):

Byoung-Shik Shim ◽

Young-Chan Kwon ◽

Michael J. Ricciardi ◽

Mars Stone ◽

Yuka Otsuka ◽

...

Keyword(s):

Zika Virus ◽

Passive Immunization ◽

The Body ◽

Transmission Model ◽

Plasma Samples ◽

Zikv Infection ◽

Fetal Demise ◽

Antibody Dependent Enhancement ◽

Pregnant Mice ◽

Asymptomatic Individuals

ABSTRACT Preexisting immunity against dengue virus or West Nile virus was previously reported to mediate antibody-dependent enhancement (ADE) of Zika virus (ZIKV) infection in a mouse model. We show here that ZIKV-immune plasma samples from both symptomatic and asymptomatic individuals mediated ZIKV ADE of infection in vitro and in mice. In a lethal infection model with a viral inoculum 10 times higher, both ADE and protection were observed, depending on the amount of infused immune plasma. In a vertical-transmission model, ZIKV-immune plasma infused to timed pregnant mice increased fetal demise and decreased the body weight of surviving fetuses. Depletion of IgG from an immune plasma abolished ADE of infection, and the presence of purified IgG alone mediated ADE of infection. Higher viral loads and proinflammatory cytokines were detected in mice treated with ZIKV-immune plasma samples compared to those receiving control plasma. Together, these data show that passive immunization with homotypic ZIKV antibodies, depending on the concentration, could either worsen or limit a subsequent ZIKV infection. IMPORTANCE Antibody-dependent enhancement (ADE) of virus infection is common to many viruses and is problematic when plasma antibody levels decline to subneutralizing concentrations. ADE of infection is especially important among flaviviruses, many of which are the cause of global health problems. Recently, human plasma samples immune to heterologous flaviviruses were shown to promote Zika virus (ZIKV) infection. Here we showed in immunocompromised mouse models that homologous immune plasma samples protect mice from subsequent infection at high antibody concentrations but that they mediate ADE of infection and increase ZIKV pathogenesis in adult mice and fetal demise during pregnancy at low concentrations.

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Impact of Zika Virus Infection on Human Neural Stem Cell MicroRNA Signatures

Viruses ◽

10.3390/v12111219 ◽

2020 ◽

Vol 12 (11) ◽

pp. 1219

Author(s):

Denna Tabari ◽

Catharina Scholl ◽

Michael Steffens ◽

Sandra Weickhardt ◽

Fabian Elgner ◽

...

Keyword(s):

Zika Virus ◽

Viral Infections ◽

Cell Communication ◽

French Polynesia ◽

Host Responses ◽

Zikv Infection ◽

Regulate Gene Expression ◽

Mediate Cell ◽

And Oxidative Stress ◽

Mrna Transcriptome

Zika virus (ZIKV) is a mosquito-borne virus, which can cause brain abnormalities in newborns, including microcephaly. MicroRNAs (miRNAs) are small non-coding RNAs, which post- transcriptionally regulate gene expression. They are involved in various processes including neurological development and host responses to viral infection, but their potential role in ZIKV pathogenesis remains poorly understood. MiRNAs can be incorporated into extracellular vesicles (EVs) and mediate cell-to-cell communication. While it is well known that in viral infections EVs carrying miRNAs can play a crucial role in disease pathogenesis, ZIKV effects on EV-delivered miRNAs and their contribution to ZIKV pathogenesis have not been elucidated. In the present study, we profiled intracellular and EV-derived miRNAs by next generation sequencing and analyzed the host mRNA transcriptome of neural stem cells during infection with ZIKV Uganda and French Polynesia strains. We identified numerous miRNAs, including miR-4792, which were dysregulated at the intracellular level and had altered levels in EVs during ZIKV infection. Integrated analyses of differentially expressed genes and miRNAs showed that ZIKV infection had an impact on processes associated with neurodevelopment and oxidative stress. Our results provide insights into the roles of intracellular and EV-associated host miRNAs in ZIKV pathogenesis.

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Clinical Outcomes of a Zika Virus Mother–Child Pair Cohort in Spain

Pathogens ◽

10.3390/pathogens9050352 ◽

2020 ◽

Vol 9 (5) ◽

pp. 352 ◽

Cited By ~ 1

Author(s):

Antoni Soriano-Arandes ◽

Marie Antoinette Frick ◽

Milagros García López-Hortelano ◽

Elena Sulleiro ◽

Carlota Rodó ◽

...

Keyword(s):

Zika Virus ◽

Adverse Outcomes ◽

Zikv Infection ◽

Child Pair ◽

Referral Hospitals ◽

Congenital Zika Syndrome ◽

Endemic Areas ◽

Neurodevelopmental Abnormalities ◽

Congenital Microcephaly

Background: Zika virus (ZIKV) infection has been associated with congenital microcephaly and other neurodevelopmental abnormalities. There is little published research on the effect of maternal ZIKV infection in a non-endemic European region. We aimed to describe the outcomes of pregnant travelers diagnosed as ZIKV-infected in Spain, and their exposed children. Methods: This prospective observational cohort study of nine referral hospitals enrolled pregnant women (PW) who travelled to endemic areas during their pregnancy or the two previous months, or those whose sexual partners visited endemic areas in the previous 6 months. Infants of ZIKV-infected mothers were followed for about two years. Results: ZIKV infection was diagnosed in 163 PW; 112 (70%) were asymptomatic and 24 (14.7%) were confirmed cases. Among 143 infants, 14 (9.8%) had adverse outcomes during follow-up; three had a congenital Zika syndrome (CZS), and 11 other potential Zika-related outcomes. The overall incidence of CZS was 2.1% (95%CI: 0.4–6.0%), but among infants born to ZIKV-confirmed mothers, this increased to 15.8% (95%CI: 3.4–39.6%). Conclusions: A nearly 10% overall risk of neurologic and hearing adverse outcomes was found in ZIKV-exposed children born to a ZIKV-infected traveler PW. Longer-term follow-up of these children is needed to assess whether there are any later-onset manifestations.

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Zika Virus Infection in the Elderly: Possible Relationship with Guillain-Barré Syndrome

Gerontology ◽

10.1159/000453579 ◽

2016 ◽

Vol 63 (3) ◽

pp. 210-215 ◽

Cited By ~ 7

Author(s):

Wilson Savino ◽

Carolina V. Messias ◽

Daniella A. Mendes-da-Cruz ◽

Pamela Passos ◽

Ana Carolina A.F. Ferreira ◽

...

Keyword(s):

Zika Virus ◽

Severe Disease ◽

The Elderly ◽

French Polynesia ◽

Therapeutic Interventions ◽

Guillain Barre Syndrome ◽

Zikv Infection ◽

Susceptible Population ◽

Guillain Barré Syndrome ◽

Guillain Barré

The Zika virus (ZIKV) outbreak in French Polynesia, in 2013, and in Brazil, in 2015, was correlated with neurological complications, which comprised, among others, congenital microcephaly and Guillain-Barré syndrome (GBS), which includes a group of acute autoimmune neuropathies generally reported after respiratory or gastrointestinal infectious diseases. Despite being relatively rare, the incidence rate of GBS rises with age, which makes GBS more frequent in the elderly, in whom it is also a more severe disease with slower recovery than in younger patients. Different forms of GBS have been described having diagnostic confirmation of a previous infection with the ZIKV virus. Although we do not have enough evidence that elderly people are a particularly susceptible population to developing GBS following ZIKV infection, this is plausible. We should consider this possibility, particularly taking into account that aging subjects are more susceptible to infections. In this context, a deeper understanding of how the immune system in the elderly functions in relation to ZIKV infection is necessary, as well as an understanding of what kind of alterations of the nervous system such an infection triggers in the elderly, beyond GBS. This will be relevant for better therapeutic interventions and for designing vaccine candidates that can be applied in an aging population, particularly those prone to develop ZIKV-induced autoimmunity.

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Recombinant Zika Virus Subunits Are Immunogenic and Efficacious in Mice

mSphere ◽

10.1128/msphere.00576-17 ◽

2018 ◽

Vol 3 (1) ◽

Cited By ~ 21

Author(s):

Albert To ◽

Liana O. Medina ◽

Kenji O. Mfuh ◽

Michael M. Lieberman ◽

Teri Ann S. Wong ◽

...

Keyword(s):

Zika Virus ◽

Neutralizing Antibodies ◽

Vaccine Candidate ◽

French Polynesia ◽

Protein Vaccine ◽

Zikv Infection ◽

Excellent Safety Profile ◽

The Caribbean ◽

Specific Antiviral Therapy

The recent outbreaks of Zika virus (ZIKV) infection in French Polynesia, the Caribbean, and the Americas have highlighted the severe neuropathological sequelae that such an infection may cause. The development of a safe, effective ZIKV vaccine is critical for several reasons: (i) the difficulty in diagnosing an active infection due to common nonspecific symptoms, (ii) the lack of a specific antiviral therapy, and (iii) the potentially devastating pathological effects ofin uteroinfection. Moreover, a vaccine with an excellent safety profile, such as a nonreplicating, noninfectious vaccine, would be ideal for high-risk people (e.g., pregnant women, immunocompromised patients, and elderly individuals). This report describes the development of a recombinant subunit protein vaccine candidate derived from stably transformed insect cells expressing the ZIKV envelope proteinin vitro, the primary antigen to which effective virus-neutralizing antibodies are engendered by immunized animals for several other flaviviruses; the vaccine candidate elicits effective virus-neutralizing antibodies against ZIKV and provides protection against ZIKV infection in mice.

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