Comparative Analysis Between Flaviviruses Reveals Specific Neural Stem Cell Tropism for Zika Virus in the Mouse Developing Neocortex

Brault, Jean‐Baptiste; Khou, Cécile; Basset, Justine; Coquand, Laure; Fraisier, Vincent; Frenkiel, Marie-Pascale; Goud, Bruno; Manuguerra, Jean-Claude; Pardigon, Nathalie; Baffet, Alexandre D.

doi:10.1016/j.ebiom.2016.07.018

Cited by 77 publications

(69 citation statements)

References 35 publications

(46 reference statements)

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“…Our finding that radial glia are preferentially infected during early neurogenesis is consistent with experiments in cultured primary human brain cells (19), developing mouse cortex (3,20), and primary human organotypic brain slice culture (7). These studies also reported overall survival of infected radial glia, in contrast to in vitro derived neural stem cells that undergo apoptotic cell death following infection (4,5,21).…”

Section: Discussionsupporting

confidence: 78%

Zika virus cell tropism in the developing human brain and inhibition by azithromycin

Retallack

Lullo

Arias

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

457

393

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The rapid spread of Zika virus (ZIKV) and its association with abnormal brain development constitute a global health emergency. Congenital ZIKV infection produces a range of mild to severe pathologies, including microcephaly. To understand the pathophysiology of ZIKV infection, we used models of the developing brain that faithfully recapitulate the tissue architecture in early to midgestation. We identify the brain cell populations that are most susceptible to ZIKV infection in primary human tissue, provide evidence for a mechanism of viral entry, and show that a commonly used antibiotic protects cultured brain cells by reducing viral proliferation. In the brain, ZIKV preferentially infected neural stem cells, astrocytes, oligodendrocyte precursor cells, and microglia, whereas neurons were less susceptible to infection. These findings suggest mechanisms for microcephaly and other pathologic features of infants with congenital ZIKV infection that are not explained by neural stem cell infection alone, such as calcifications in the cortical plate. Furthermore, we find that blocking the glia-enriched putative viral entry receptor AXL reduced ZIKV infection of astrocytes in vitro, and genetic knockdown of AXL in a glial cell line nearly abolished infection. Finally, we evaluate 2,177 compounds, focusing on drugs safe in pregnancy. We show that the macrolide antibiotic azithromycin reduced viral proliferation and virusinduced cytopathic effects in glial cell lines and human astrocytes. Our characterization of infection in the developing human brain clarifies the pathogenesis of congenital ZIKV infection and provides the basis for investigating possible therapeutic strategies to safely alleviate or prevent the most severe consequences of the epidemic.A correlation between congenital exposure to the mosquitoborne and sexually transmitted Zika flavivirus (ZIKV) and the increased incidence of severe microcephaly suggests a causal relationship between ZIKV infection and neurodevelopmental abnormalities (1, 2). However, the mechanisms of infection and specifically which cell populations are vulnerable to ZIKV during the course of human brain development remain unclear. Major insights have been drawn from in vitro models of human brain development and primary mouse tissues. In the developing mouse brain, ZIKV has been shown to infect radial glia and neurons (3), whereas studies in human pluripotent stem cell (hPSC)-derived neural cells have highlighted widespread infection and apoptosis of neural progenitor cells (4,5). Because these models do not fully recapitulate the developmental events and cell types present during human brain development, these results may not faithfully represent ZIKV-induced pathology in vivo.During human brain development, radial glial cells, the neural stem cells, give rise to diverse types of neuronal and glial cells, including neurons, oligodendrocytes, and astrocytes, in a temporally controlled pattern. We reasoned that identifying cell types that are especially vulnerable to viral infection wou...

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Section: Discussionsupporting

confidence: 78%

Zika virus cell tropism in the developing human brain and inhibition by azithromycin

Retallack

Lullo

Arias

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

457

393

View full text Add to dashboard Cite

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“…Induction of caspase 3 cleavage occurred mostly within the cells that surround the virus-infected cell (Fig. 3), which has also been suggested by the results of other studies (30,31). These regions of apoptosis were confined to areas marked by ZIKV-E staining, as seen in the neocortex of an organotypic slice infected with the Malaysian isolate (Fig.…”

Section: Resultssupporting

confidence: 61%

“…2C). Poliovirus was used as a negative control, as the related flavivirus dengue was previously shown not to replicate in embryonic brain slices (30). Poliovirus did not replicate in brain slice cultures, as the mice used do not produce the poliovirus receptor, CD155 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…ZIKV-associated neuronal dysfunction may develop postnatally, and there remains a lack of understanding of the long-term cognitive and physical disabilities associated with cZVS (41). Many models of ZIKV infection have been established but none have or can systematically examine the consequences of viral infection across pre-and postnatal brain development (16,30,42).…”

Section: Discussionmentioning

confidence: 99%

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Replication of early and recent Zika virus isolates throughout mouse brain development

Rosenfeld

Doobin

Warren

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Fetal infection with Zika virus (ZIKV) can lead to congenital Zika virus syndrome (cZVS), which includes cortical malformations and microcephaly. The aspects of cortical development that are affected during virus infection are unknown. Using organotypic brain slice cultures generated from embryonic mice of various ages, sites of ZIKV replication including the neocortical proliferative zone and radial columns, as well as the developing midbrain, were identified. The infected radial units are surrounded by uninfected cells undergoing apoptosis, suggesting that programmed cell death may limit viral dissemination in the brain and may constrain virus-associated injury. Therefore, a critical aspect of ZIKV-induced neuropathology may be defined by death of uninfected cells. All ZIKV isolates assayed replicated efficiently in early and midgestation cultures, and two isolates examined replicated in late-gestation tissue. Alteration of neocortical cytoarchitecture, such as disruption of the highly elongated basal processes of the radial glial progenitor cells and impairment of postmitotic neuronal migration, were also observed. These data suggest that all lineages of ZIKV tested are neurotropic, and that ZIKV infection interferes with multiple aspects of neurodevelopment that contribute to the complexity of cZVS.

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“…As a result, these genetic syndromes are often associated with a reduction in number of neuroprogenitor cells. Zika virus appears to behave in much the same way 5,6 , by targeting for infection those cells most vulnerable for injury, and whose numbers cannot be replaced.…”

mentioning

confidence: 99%

Congenital Zika syndrome: an epidemic of neurologic disability

Paciorkowski

2017

Arq. Neuro-Psiquiatr.

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Comparative Analysis Between Flaviviruses Reveals Specific Neural Stem Cell Tropism for Zika Virus in the Mouse Developing Neocortex

Cited by 77 publications

References 35 publications

Zika virus cell tropism in the developing human brain and inhibition by azithromycin

Zika virus cell tropism in the developing human brain and inhibition by azithromycin

Replication of early and recent Zika virus isolates throughout mouse brain development

Congenital Zika syndrome: an epidemic of neurologic disability

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