Embryonic and Neonatal Mouse Cochleae Are Susceptible to Zika Virus Infection

Congenital Zika Syndrome (CZS) is caused by vertical transmission of Zika virus (ZIKV) to the gestating human fetus. A subset of CZS microcephalic infants present with reduced otoacoustic emissions; this test screens for hearing loss originating in the cochlea. This observation leads to the question of whether mammalian cochlear tissues are susceptible to infection by ZIKV during development. To address this question using a mouse model, the sensory cochlea was explanted at proliferative, newly post-mitotic or maturing stages. ZIKV was added for the first 24 h and organs cultured for up to 6 days to allow for cell differentiation. Results showed that ZIKV can robustly infect proliferating sensory progenitors, as well as post-mitotic hair cells and supporting cells. Virus neutralization using ZIKV-117 antibody blocked cochlear infection. AXL is a cell surface molecule known to enhance the attachment of flavivirus to host cells. While Axl mRNA is widely expressed in embryonic cochlear tissues susceptible to ZIKV infection, it is selectively downregulated in the post-mitotic sensory organ by E15.5, even though these cells remain infectible. These findings may offer insights into which target cells could potentially contribute to hearing loss resulting from fetal exposure to ZIKV in humans.

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

10.1101/387118 ◽

2018 ◽

Cited By ~ 1

Author(s):

Anna S. Jaeger ◽

Reyes A. Murreita ◽

Lea R. Goren ◽

Chelsea M. Crooks ◽

Ryan V. Moriarty ◽

...

Keyword(s):

Mouse Model ◽

Vertical Transmission ◽

Birth Defects ◽

Asian American ◽

Zika Virus ◽

French Polynesia ◽

Transmission Model ◽

Foreseeable Future ◽

Zikv Infection ◽

Congenital Zika Syndrome

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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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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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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Adaptation to host cell environment during experimental evolution of Zika virus

10.21203/rs.3.rs-492894/v1 ◽

2021 ◽

Author(s):

Vincent Grass ◽

Emilie Hardy ◽

Kassian Kobert ◽

Soheil Rastgou Talemi ◽

Elodie Décembre ◽

...

Keyword(s):

Host Cell ◽

Zika Virus ◽

Immune Escape ◽

Viral Evolution ◽

Time Lag ◽

Host Cells ◽

Host Responses ◽

Type I ◽

Zikv Infection ◽

Cellular Environment

Abstract Zika virus (ZIKV) infection can cause important developmental and neurological defects in Humans. Type I/III interferon responses control ZIKV infection and pathological processes, yet the virus has evolved various mechanisms to defeat these host responses. Here, we established a pipeline to delineate at high-resolution the genetic evolution of ZIKV in a controlled host cell environment. We uncovered that serially passaged ZIKV acquired increased infectivity and simultaneously developed a resistance to TLR3-induced restriction. We built a mathematical model that suggests that the increased infectivity is due to a reduced time-lag between infection and viral replication. We found that this adaptation is cell-type specific, suggesting that different cell environments may drive viral evolution along different routes. Deep-sequencing of ZIKV populations pinpointed mutations whose increased frequencies temporally coincide with the acquisition of the adapted phenotype. We functionally validated S455L, a substitution in ZIKV envelope (E) protein, recapitulating the adapted phenotype. Its positioning on the E structure suggests a putative function in protein refolding/stability. Taken together, our results uncovered ZIKV adaptations to the cellular environment leading to accelerated replication onset coupled with resistance to TLR3-induced antiviral response. Our work provides insights into Zika virus adaptation to host cells and immune escape mechanisms.

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ADP-Ribosyltransferase PARP11 Suppresses Zika Virus in Synergy with PARP12

10.21203/rs.3.rs-385154/v1 ◽

2021 ◽

Author(s):

Lili Li ◽

Yueyue Shi ◽

Sirui Li ◽

Junxiao Liu ◽

Shulong Zu ◽

...

Keyword(s):

Zika Virus ◽

Neurological Complications ◽

Host Cells ◽

Interferon Response ◽

Type I ◽

Zikv Infection ◽

Interferon Stimulated Genes ◽

Ns3 Protein ◽

Global Threat ◽

Adp Ribosyltransferase

Abstract Zika virus (ZIKV) infection and ZIKV epidemic have been continuously spreading silently throughout the world and its associated microcephaly and other serious congenital neurological complications poses a significant global threat to public health. ZIKV infection stimulates type I interferon response in host cells which suppresses viral replication by inducing the expression of interferon-stimulated genes (ISGs). Here, we identified ADP-ribosyltransferase PARP11 as an anti-ZIKV ISG and found that PARP11 suppressed ZIKV independently on itself PARP enzyme activity. Furthermore, PARP11 interacted with PARP12 and promoted PARP12-mediating ZIKV NS1 and NS3 protein degradation. Homo family PARP11 and PARP12 cooperated with each other on ZIKV suppression and the anti-ZIKV function of PARP11 mostly dependent on the existence of PARP12. Our findings have broadened the understanding of the anti-viral function of PARP11, and more importantly suggest a potential therapeutics target against ZIKV infection.

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ADP-ribosyltransferase PARP11 suppresses Zika virus in synergy with PARP12

Cell & Bioscience ◽

10.1186/s13578-021-00628-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Lili Li ◽

Yueyue Shi ◽

Sirui Li ◽

Junxiao Liu ◽

Shulong Zu ◽

...

Keyword(s):

Protein Degradation ◽

Cell Lines ◽

Zika Virus ◽

Hek293t Cell ◽

Host Cells ◽

Interferon Response ◽

Type I ◽

Zikv Infection ◽

Ns3 Protein ◽

Adp Ribosyltransferase

Abstract Background Zika virus (ZIKV) infection and ZIKV epidemic have been continuously spreading silently throughout the world and its associated microcephaly and other serious congenital neurological complications poses a significant global threat to public health. Type I interferon response to ZIKV infection in host cells suppresses viral replication by inducing the expression of interferon-stimulated genes (ISGs). Methods The study aims to demonstrate the anti-ZIKV mechanism of PARP11. PARP11 knock out and overexpressing A549 cell lines were constructed to evaluate the anti-ZIKV function of PARP11. PARP11−/−, PARP12−/− and PARP11−/−PARP12−/− HEK293T cell lines were constructed to explain the synergistic effect of PARP11 and PARP12 on NS1 and NS3 protein degradation. Western blotting, immunofluorescence and immunoprecipitation assay were performed to illustrate the interaction between PARP11 and PARP12. Results Both mRNA and protein levels of PARP11 were induced in WT but not IFNAR1−/− cells in response to IFNα or IFNβ stimulation and ZIKV infection. ZIKV replication was suppressed in cells expressed PARP11 but was enhanced in PARP11−/− cells. PARP11 suppressed ZIKV independently on itself PARP enzyme activity. PARP11 interacted with PARP12 and promoted PARP12-mediated ZIKV NS1 and NS3 protein degradation. Conclusion We identified ADP-ribosyltransferase PARP11 as an anti-ZIKV ISG and found that it cooperated with PARP12 to enhance ZIKV NS1 and NS3 protein degradation. Our findings have broadened the understanding of the anti-viral function of ADP-ribosyltransferase family members, and provided potential therapeutic targets against viral ZIKV infection.

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

10.1101/2020.10.20.20214403 ◽

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.

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Human neutrophils are not activated by Zika virus but reduce the infection of susceptible cells

10.1101/2021.09.26.461875 ◽

2021 ◽

Author(s):

Juliana Bernardi Aggio ◽

Bárbara Nery Porto ◽

Claudia Nunes Duarte dos Santos ◽

Ana Luiza Pamplona Mosimann ◽

Pryscilla Fanini Wowk

Keyword(s):

Zika Virus ◽

Neutrophil Migration ◽

A549 Cells ◽

Human Neutrophils ◽

Cell Contact ◽

Target Cells ◽

Zikv Infection ◽

Host Interaction

Zika virus (ZIKV) emergence highlighted the need for a deeper understanding on virus-host interaction to pave the development of antiviral therapies. The present work aimed to address the response of neutrophils during ZIKV infection. Neutrophils are an important effector cell in innate immunity involved in the host response to neurotropic arboviruses. Our results indicate that human neutrophils were not permissive to Asian or African ZIKV strains replication. Indeed, after stimulation with ZIKV, neutrophils were not primed against the virus as evaluated by the absence of CD11b modulation, secretion of inflammatory cytokines and granule content, production of reactive oxygen species and neutrophil extracellular traps formation. Overall, neutrophils did not affect ZIKV infectivity. Moreover, ZIKV infection of primary innate immune cells in vitro did not trigger neutrophil migration. However, neutrophil co-cultured with ZIKV susceptible cells (A549) resulted in lower frequencies of infection on A549 cells by cell-to-cell contact. In vivo, neutrophil depletion from immunocompetent mice did not affect ZIKV spreading to the draining lymph nodes. The data suggest human neutrophils do not play a per se antiviral role against ZIKV, but these cells might participate in an infected environment shaping the ZIKV infection in other target cells.

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Zika virus infection from a newborn point of view. TORCH or TORZiCH?

Interdisciplinary Toxicology ◽

10.2478/intox-2018-0023 ◽

2018 ◽

Vol 11 (4) ◽

pp. 241-246 ◽

Cited By ~ 2

Author(s):

Adriana Tahotná ◽

Jana Brucknerová ◽

Ingrid Brucknerová

Keyword(s):

Virus Infection ◽

Zika Virus ◽

Clinical Symptoms ◽

Global Climate ◽

Point Of View ◽

Zikv Infection ◽

Global Climate Changes ◽

Zika Virus Infection ◽

Congenital Zika Syndrome ◽

The Media

Abstract Zika virus (ZIKV) belongs to the group of viruses called arboviruses. Congenital Zika syndrome is a new disease with infectious teratogenic aetiology. The clinical symptoms are divided into morphological and functional. Most severe complication is the foetal brain disruption sequence that includes severe microcephaly, anomalies of the eyes and congenital contractions of joints. The aim of this paper was to review available facts about Zika virus infection from a newborn point of view in a form of the summary of all important information. Zika virus infection is a problem of past, present and future. Epidemics may occur because of global climate changes, also in countries where natural conditions for life of mosquitos are not present. This clearly indicates the need to continue developing of vaccines and specific antiviral drugs. Until this happens, we must adhere individual preventive measures. Zika virus has proven to us how it can affect the health of adults and neonates but also thinking of healthy people. Newborns with microcephaly on the front pages of the media caused in 2015 panic and fear around the world – for this reason education of people is necessary. Due to serious congenital disorders associated with ZIKV infection and global impact of virus we suggest modifying old acronym TORCH for new TORZiCH to accent the position of Zika virus.

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