Neurodevelopment in Normocephalic Children Exposed to Zika Virus in Utero with No Observable Defects at Birth: A Systematic Review with Meta-Analysis

Marbán-Castro, Elena; Guillamet, Laia Jimena Vazquez; Pantoja, Percy Efrain; Casellas, Aina; Maxwell, Lauren; Mulkey, Sarah B.; Menéndez, Clara; Bardají, Azucena

doi:10.3390/ijerph19127319

Cited by 18 publications

(23 citation statements)

References 41 publications

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“…To characterize the sensitivity of human astrocytes to ZIKV infection during different developmental periods, we used pure astrocytes cultures or mixed cultures of human neurons and astrocytes obtained at different developmental stages to determine their infectivity and viral replication. Figure 1 represents a time course summary of ZIKV congenital syndrome as described [ 4 , 29 , 45 , 53 ]. We denote the timeline of gestation (arrows), neurogenesis, astrogenesis, growth and differentiation, and the correlation of these neurodevelopmental stages with ZIKV infection and brain abnormalities detected by ultrasound and our studies between 16 and 22 weeks post-conception, wpc ( Figure 1 ).…”

Section: Resultsmentioning

confidence: 99%

“…Zika virus (ZIKV) was declared a Public Health Emergency by the World Health Organization (W.H.O.) from February 2016 to March 2017 [ 1 , 2 ]; however, the emergence of new viruses such as SARS-CoV-2 has reduced the interest in ZIKV despite its devastating consequences during developmental stages [ 3 ], [ 4 ], [ 5 ], [ 6 ], [ 7 ]. Despite the multiple outbreaks and epidemic proportions of ZIKV worldwide, the mechanism by which this virus compromises the developing brain only recently has been explored [ 8 ], [ 9 ], [ 10 ], [ 11 ], [ 12 ], [ 13 ], [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

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Mechanisms of Zika astrocyte infection and neuronal toxicity

Veilleux

Eugenin

2022

NeuroImmune Pharmacology and Therapeutics

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Objectives Zika virus (ZIKV) has become an epidemic in several countries and was declared a major public health issue by the WHO. Although ZIKV infection is asymptomatic or shows mild fever-related symptoms in most people, the virus can be transmitted from a pregnant mother to the fetus, resulting in severe brain developmental abnormalities, including microcephaly. Multiple groups have identified developmental neuronal and neuronal progenitor compromise during ZIKV infection within the fetal brain, but little is known about whether ZIKV could infect human astrocytes and its effect on the developing brain. Thus, our objective was to determine astrocyte ZiKV infection in a developmental-dependent manner. Methods We analyze infection of pure cultures of astrocytes and mixed cultures of neurons and astrocytes in response to ZIKV using plaque assays, confocal, and electron microscopy to identify infectivity, ZIKV accumulation and intracellular distribution as well as apoptosis and interorganelle dysfunction. Results Here, we demonstrated that ZIKV enters, infects, replicates, and accumulates in large quantities in human fetal astrocytes in a developmental-dependent manner. Astrocyte infection and intracellular viral accumulation resulted in neuronal apoptosis, and we propose astrocytes are a ZIKV reservoir during brain development. Conclusions Our data identify astrocytes in different stages of development as major contributors to the devastating effects of ZIKV in the developing brain.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mechanisms of Zika astrocyte infection and neuronal toxicity

Veilleux

Eugenin

2022

NeuroImmune Pharmacology and Therapeutics

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“…However, it seems likely that at least those opossums with severe brain pathologies would exhibit abnormalities in behavior, social interactions, cognitive abilities, and memory if they were allowed to develop and were rigorously assessed. Recently, it has been demonstrated that some children who were exposed in utero to ZIKV and were not born with CZS exhibit delayed neurodevelopment and neurosensory alterations by the second year of life [ 42 ], and that some may have altered “executive function, mood, and adaptive mobility” by ages 3–5 years [ 43 ]. As a practical, non-genetically modified animal model that has a relatively short lifespan and can be utilized in large numbers, the opossum may prove to be critical for research on the long-term effects of in utero ZIKV infection on childhood development and into adulthood.…”

Section: Discussionmentioning

confidence: 99%

Monodelphis domestica as a Fetal Intra-Cerebral Inoculation Model for Zika Virus Pathogenesis

et al. 2023

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Monodelphis domestica (the laboratory opossum) is a marsupial native to South America. At birth, these animals are developmentally equivalent to human embryos at approximately 5 weeks of gestation, which, when coupled with other characteristics including the size of the animals, the development of a robust immune system during juvenile development, and the relative ease of experimental manipulation, have made M. domestica a valuable model in many areas of biomedical research. However, their suitability as models for infectious diseases, especially neurotropic viruses such as Zika virus (ZIKV), is currently unknown. Here, we describe the replicative effects of ZIKV using a fetal intra-cerebral model of inoculation. Using immunohistology and in situ hybridization, we found that opossum embryos and fetuses are susceptible to infection by ZIKV administered intra-cerebrally, that the infection persists, and that viral replication results in neural pathology and may occasionally result in global growth restriction. These results demonstrate the utility of M. domestica as a new animal model for investigating ZIKV infection in vivo and facilitate further inquiry into viral pathogenesis, particularly for those viruses that are neurotropic, that require a host with the ability to sustain sustained viremia, and/or that may require intra-cerebral inoculations of large numbers of embryos or fetuses.

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“…A study of 70 Colombian infants with confirmed exposure to ZIKV during the pregnancy without CZS, assessed using the Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA) up to 18 months found that there was a progressive deviation from normative levels on the WIDEA total, mobility, communication, and social cognition scores over time [75 ▪ ]. Meta-analysis of neurodevelopment in normocephalic children with prenatal ZIKV exposure found cognitive, language, or motor delay on Bayley-III in 6.5, 29.7, and 11.5% of children, respectively [76 ▪▪ ]. Reports of outcomes at older ages are beginning to appear.…”

Section: Neurological and Developmental Outcomes Of Congenital Infect...mentioning

confidence: 99%

Neurodevelopmental outcomes in congenital and perinatal infections

Fortin

Mulkey

2023

Current Opinion in Infectious Diseases

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Purpose of review Congenital infections are a major cause of childhood multidomain neurodevelopmental disabilities. They contribute to a range of structural brain abnormalities that can cause severe neurodevelopmental impairment, cerebral palsy, epilepsy, and neurosensory impairments. New congenital infections and global viral pandemics have emerged, with some affecting the developing brain and causing neurodevelopmental concerns. This review aims to provide current understanding of fetal infections and their impact on neurodevelopment. Recent findings There are a growing list of congenital infections causing neurodevelopmental issues, including cytomegalovirus, Zika virus, syphilis, rubella, lymphocytic choriomeningitis virus, and toxoplasmosis. Fetal exposure to maternal SARS-CoV-2 may also pose risk to the developing brain and impact neurodevelopmental outcomes, although studies have conflicting results. As Zika virus was a recently identified congenital infection, there are several new reports on child neurodevelopment in the Caribbean and Central and South America. For many congenital infections, children with in-utero exposure, even if asymptomatic at birth, may have neurodevelopmental concerns manifest over time. Summary Congenital infections should be considered in the differential diagnosis of a child with neurodevelopmental impairments. Detailed pregnancy history, exposure risk, and testing should guide diagnosis and multidisciplinary evaluation. Children with congenital infections should have long-term follow-up to assess for neurodevelopmental delays and other neurosensory impairments. Children with confirmed delays or high-risk should be referred for rehabilitation therapies.

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Neurodevelopment in Normocephalic Children Exposed to Zika Virus in Utero with No Observable Defects at Birth: A Systematic Review with Meta-Analysis

Cited by 18 publications

References 41 publications

Mechanisms of Zika astrocyte infection and neuronal toxicity

Mechanisms of Zika astrocyte infection and neuronal toxicity

Monodelphis domestica as a Fetal Intra-Cerebral Inoculation Model for Zika Virus Pathogenesis

Neurodevelopmental outcomes in congenital and perinatal infections

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