Abstract
Zika virus (ZIKV) infection of pregnant women and diaplazental transmission to the fetus is linked to the congenital syndrome of microcephaly in newborns. This neuropathology is believed to result from significant death of neuronal progenitor cells (NPC). Here, we examined the fate of neurons in the developing hippocampus, a brain structure which houses neuronal populations of different maturation states. For this purpose, we infected hippocampal slice cultures from immunocompetent newborn mice with ZIKV and monitored changes in hippocampal architecture. In neurons of all hippocampal subfields ZIKV was detected by immunofluorescence labeling and electron microscopy. This includes pyramidal neurons that maturate during the embryonic phase. In the dentate gyrus, ZIKV could be found in the Cajal–Retzius (CR) cells which belong to the earliest born cortical neurons, but also in granule cells that are predominantly generated postnatally. Intriguingly, virus particles were also present in the correctly outgrowing mossy fiber axons of juvenile granule cells, suggesting that viral infection does not impair region- and layer-specific formation of this projection. ZIKV infection of hippocampal tissue was accompanied by both a profound astrocyte reaction indicating tissue injury and a microglia response suggesting phagocytotic activity. Furthermore, depending on the viral load and incubation time, we observed extensive overall neuronal loss in the cultured hippocampal slice cultures. Thus, we conclude ZIKV can replicate in various neuronal populations and trigger neuronal death independent of the maturation state of infected cells.
Highlights
Zika virus (ZIKV), a member of the Flavivirus genus within the Flaviviridae family was identified almost 70 years ago in Africa, but severe diseases were not reported
After infection of the cultures with 103 plaque forming units (PFU) of ZIKV, virus-positive cells were detected by immunostaining in granule cells of the dentate gyrus 7 days p.i. (Figure 1A)
That these features are maintained in long-term hippocampal slice cultures (Gähwiler, 1984; Frotscher et al, 1995), this ex vivo approach has been successfully used for investigating virus mediated neuronal pathologies (Mayer et al, 2005; Wu et al, 2013)
Summary
Zika virus (ZIKV), a member of the Flavivirus genus within the Flaviviridae family was identified almost 70 years ago in Africa, but severe diseases were not reported. Infections of Neurons by Zika Virus limb postures and severe sensory defects. Flaviviruses induce structural changes of the endoplasmic reticulum (ER) including convoluted membranes (CMs) and socalled vesicle packets (VPs), the presumed sites of viral RNA replication (Paul and Bartenschlager, 2013; Hamel et al, 2015). Using Huh human hepatic cells and human neuronal progenitor cells (NPC), a physiologically relevant target of ZIKV, Cortese et al (2017) could show that ZIKV infection induces reorganization of the ER to form VPs and CMs and affects intermediate filaments and microtubule network organelles to enable robust virus amplification. Preventing structural alterations by cytoskeleton stabilizing molecules suppresses ZIKV replication (Cortese et al, 2017)
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