Zika virus infection impairs synaptogenesis, induces neuroinflammation, and could be an environmental risk factor for autism spectrum disorder outcome.

Zika virus (ZIKV) infection was first associated with Central Nervous System (CNS) infections in Brazil in 2015, correlated with an increased number of newborns with microcephaly, which ended up characterizing the Congenital Zika Syndrome (CZS). Here, we investigated the impact of ZIKV infection on the functionality of iPSC-derived astrocytes. Besides, we extrapolated our findings to a Brazilian cohort of 136 CZS children and validated our results using a mouse model. Interestingly, ZIKV infection in neuroprogenitor cells compromises cell migration and causes apoptosis but does not interfere in astrocyte generation. Moreover, infected astrocytes lost their ability to uptake glutamate while expressing more glutamate transporters and secreted higher levels of IL-6. Besides, infected astrocytes secreted factors that impaired neuronal synaptogenesis. Since these biological endophenotypes were already related to Autism Spectrum Disorder (ASD), we extrapolated these results to a cohort of children, now 6-7 years old, and found seven children with ASD diagnosis (5.14 %). Additionally, mice infected by ZIKV revealed autistic-like behaviors, with a significant increase of IL-6 mRNA levels in the brain. Considering these evidence, we inferred that ZIKV infection during pregnancy might lead to synaptogenesis impairment and neuroinflammation, which could increase the risk for ASD.

microRNAs Control Antiviral Immune Response, Cell Death and Chemotaxis Pathways in Human Neuronal Precursor Cells (NPCs) during Zika Virus Infection.

Viral infections have always been a serious burden to public health, increasing morbidity and mortality rates worldwide. Zika virus (ZIKV) is a flavivirus transmitted by the Aedes aegypti vector and the causative agent of severe fetal neuropathogenesis and microcephaly. The virus crosses the placenta and reaches the fetal brain, mainly causing the death of neuronal precursor cells (NPCs), glial inflammation, and subsequent tissue damage. Genetic differences, mainly related to the antiviral immune response and cell death pathways greatly influence the susceptibility to infection. These components are modulated by many factors, including microRNAs (miRNAs). MiRNAs are small noncoding RNAs that regulate post-transcriptionally the overall gene expression, including genes for the neurodevelopment and the formation of neural circuits. In this context, we investigated the pathways and target genes of miRNAs modulated in NPCs infected with ZIKV. We observed downregulation of miR-302b, miR-302c and miR-194, whereas miR-30c was upregulated in ZIKV infected human NPCs in vitro. The analysis of a public dataset of ZIKV-infected human NPCs evidenced 262 upregulated and 3 downregulated genes, of which 142 were the target of the aforementioned miRNAs. Further, we confirmed a correlation between miRNA and target genes affecting pathways related to antiviral immune response, cell death and immune cells chemotaxis, all of which could contribute to the establishment of microcephaly and brain lesions. Here, we suggest that miRNAs target gene expression in infected NPCs, directly contributing to the pathogenesis of fetal microcephaly.

An update on preclinical pregnancy models of Zika virus infection for drug and vaccine discovery.

INTRODUCTION: Congenital Zika syndrome is caused by Zika virus (ZIKV) infection during pregnancy and can culminate in structural and neurological defects in the fetus, including a spectrum of symptoms such as brain calcifications, hydrocephalus, holoprosencephaly, lissencephaly, ventriculomegaly, and microcephaly. Using animal models to study ZIKV infection during pregnancy represents a critical tool for understanding ZIKV pathophysiology, drug testing, vaccine development, and prevention of vertical transmission. AREAS COVERED: In this review, the authors cover state-of-the-art preclinical pregnancy models of ZIKV infection for drug discovery and vaccine development to prevent vertical transmission. EXPERT OPINION: The discovery of drugs against ZIKV infection represents an urgent necessity, and until now, no effective drug that can prevent the effects of vertical transmission has been tested in humans. Even after six years of the ZIKV outbreak in Brazil, no drugs or vaccines have been approved for use in humans. In part, this failure could be related to the lack of translatability from available preclinical models to humans.

Developing animal models of Zika virus infection for novel drug discovery.

INTRODUCTION: Just before the Brazilian outbreak, Zika virus was related to a mild infection, causing fever and skin rash. Congenital Zika Syndrome was first described in Brazil, causing microcephaly and malformations in newborns. Three years after the outbreak, the mechanisms of Zika pathogenesis are still not completely elucidated. Moreover, as of today, there is still no approved vaccine that can be administered to the susceptible population. Considering the unmet clinical need, animal models represent an unprecedented opportunity to study Zika pathophysiology and test drugs for the treatment and prevention of vertical transmission. Areas covered: The authors explore the current knowledge about Zika through animal models and advancements in drug discovery by highlighting drugs with the greatest potential to treat ZIKV infection and block vertical transmission. Expert opinion: Some drugs used to treat other infections have been repurposed to treat Zika infection, reducing the cost and time for clinical application. One promising example is Sofosbuvir, which protected mice models against Zika pathogenesis by preventing vertical transmission. Importantly, there is a lack on exploration on the long-term effects of Zika Congenital Syndrome, as well as the possible ways to treat its sequelae.

The Brazilian Zika virus strain causes birth defects in experimental models.

Zika virus (ZIKV) is an arbovirus belonging to the genus Flavivirus (family Flaviviridae) and was first described in 1947 in Uganda following blood analyses of sentinel Rhesus monkeys. Until the twentieth century, the African and Asian lineages of the virus did not cause meaningful infections in humans. However, in 2007, vectored by Aedes aegypti mosquitoes, ZIKV caused the first noteworthy epidemic on the Yap Island in Micronesia. Patients experienced fever, skin rash, arthralgia and conjunctivitis. From 2013 to 2015, the Asian lineage of the virus caused further massive outbreaks in New Caledonia and French Polynesia. In 2013, ZIKV reached Brazil, later spreading to other countries in South and Central America. In Brazil, the virus has been linked to congenital malformations, including microcephaly and other severe neurological diseases, such as Guillain-Barré syndrome. Despite clinical evidence, direct experimental proof showing that the Brazilian ZIKV (ZIKV(BR)) strain causes birth defects remains absent. Here we demonstrate that ZIKV(BR) infects fetuses, causing intrauterine growth restriction, including signs of microcephaly, in mice. Moreover, the virus infects human cortical progenitor cells, leading to an increase in cell death. We also report that the infection of human brain organoids results in a reduction of proliferative zones and disrupted cortical layers. These results indicate that ZIKV(BR) crosses the placenta and causes microcephaly by targeting cortical progenitor cells, inducing cell death by apoptosis and autophagy, and impairing neurodevelopment. Our data reinforce the growing body of evidence linking the ZIKV(BR) outbreak to the alarming number of cases of congenital brain malformations. Our model can be used to determine the efficiency of therapeutic approaches to counteracting the harmful impact of ZIKV(BR) in human neurodevelopment.