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Zika virus directly infects peripheral neurons and induces cell death.

ABSTRACT: Zika virus (ZIKV) infection is associated with neurological disorders of both the CNS and peripheral nervous systems (PNS), yet few studies have directly examined PNS infection. Here we show that intraperitoneally or intraventricularly injected ZIKV in the mouse can infect and impact peripheral neurons in vivo. Moreover, ZIKV productively infects stem-cell-derived human neural crest cells and peripheral neurons in vitro, leading to increased cell death, transcriptional dysregulation and cell-type-specific molecular pathology.

SUBMITTER: Oh Y

PROVIDER: S-EPMC5575960 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Zika virus directly infects peripheral neurons and induces cell death.

Oh Yohan Y Zhang Feiran F Wang Yaqing Y Lee Emily M EM Choi In Young IY Lim Hotae H Mirakhori Fahimeh F Li Ronghua R Huang Luoxiu L Xu Tianlei T Wu Hao H Li Cui C Qin Cheng-Feng CF Wen Zhexing Z Wu Qing-Feng QF Tang Hengli H Xu Zhiheng Z Jin Peng P Song Hongjun H Ming Guo-Li GL Lee Gabsang G

Nature neuroscience 20170731 9

Zika virus (ZIKV) infection is associated with neurological disorders of both the CNS and peripheral nervous systems (PNS), yet few studies have directly examined PNS infection. Here we show that intraperitoneally or intraventricularly injected ZIKV in the mouse can infect and impact peripheral neurons in vivo. Moreover, ZIKV productively infects stem-cell-derived human neural crest cells and peripheral neurons in vitro, leading to increased cell death, transcriptional dysregulation and cell-typ ...[more]

PMID: 28758997

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Zika virus directly infects human peripheral neurons and induces cell death

Project description:Zika virus (ZIKV), a flavivirus transmitted primarily by Aedes mosquitoes, has spread to 59 countries and territories throughout the world. ZIKV-infected patients can have several symptoms and there is scientific consensus that ZIKV is a cause of microcephaly. Most studies are focusing on the central nervous system (CNS), and it is largely unknown whether ZIKV also affects the developing peripheral nervous system. Here, using a human pluripotent stem cell-based model, we demonstrated that Puerto Rican ZIKV strain, PRVABC59, efficiently infects human neural crest cells (hNCCs). In contrast to little infection of CNS neurons, ZIKV readily infects human peripheral neurons (hPNs), leading to cell death. Global gene expression analyses of infected hNCCs and hPNs reveal transcriptional dysregulation, notably of cell-death- and cell-cycle-related pathways. Our results identify hNCCs and hPNs as a direct ZIKV target and provide a framework to investigate the ZIKV pathology on the peripheral neurons.

2017-07-07 | GSE87750 | GEO

Zika Virus Infects Human Placental Macrophages.

Project description:The recent Zika virus (ZIKV) outbreak in Brazil has been directly linked to increased cases of microcephaly in newborns. Current evidence indicates that ZIKV is transmitted vertically from mother to fetus. However, the mechanism of intrauterine transmission and the cell types involved remain unknown. We demonstrate that the contemporary ZIKV strain PRVABC59 (PR 2015) infects and replicates in primary human placental macrophages, called Hofbauer cells, and to a lesser extent in cytotrophoblasts, isolated from villous tissue of full-term placentae. Viral replication coincides with induction of type I interferon (IFN), pro-inflammatory cytokines, and antiviral gene expression, but with minimal cell death. Our results suggest a mechanism for intrauterine transmission in which ZIKV gains access to the fetal compartment by directly infecting placental cells and disrupting the placental barrier.

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Zika virus infects human blood mononuclear cells.

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Zika Virus Infects Intermediate Progenitor Cells and Post-mitotic Committed Neurons in Human Fetal Brain Tissues.

Project description:Zika virus (ZIKV) infection is associated with microcephaly in fetuses, but the pathogenesis of ZIKV-related microcephaly is not well understood. Here we show that ZIKV infects the subventricular zone in human fetal brain tissues and that the tissue tropism broadens with the progression of gestation. Our research demonstrates also that intermediate progenitor cells (IPCs) are the main target cells for ZIKV. Post-mitotic committed neurons become susceptible to ZIKV infection as well at later stages of gestation. Furthermore, activation of microglial cells, DNA fragmentation, and apoptosis of infected or uninfected cells could be found in ZIKV-infected brain tissues. Our studies identify IPCs as the main target cells for ZIKV. They also suggest that immune activation after ZIKV infection may play an important role in the pathogenesis of ZIKV-related microcephaly.

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Zika virus productively infects primary human placenta-specific macrophages.

Project description:The strong association of Zika virus infection with congenital defects has led to questions of how a flavivirus is capable of crossing the placental barrier to reach the fetal brain. Here, we demonstrate permissive Zika virus infection of primary human placental macrophages, commonly referred to as Hofbauer cells, and placental villous fibroblasts. We also demonstrate Zika virus infection of Hofbauer cells within the context of the tissue ex vivo using term placental villous explants. In addition to amplifying infectious virus within a usually inaccessible area, the putative migratory activities of Hofbauer cells may aid in dissemination of Zika virus to the fetal brain. Understanding the susceptibility of placenta-specific cell types will aid future work around and understanding of Zika virus-associated pregnancy complications.

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Zika virus infects human testicular tissue and germ cells.

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Zika Virus-Mediated Death of Hippocampal Neurons Is Independent From Maturation State.

Project description: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.

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Zika Virus Infects Human Cortical Neural Progenitors and Attenuates Their Growth.

Project description:The suspected link between infection by Zika virus (ZIKV), a re-emerging flavivirus, and microcephaly is an urgent global health concern. The direct target cells of ZIKV in the developing human fetus are not clear. Here we show that a strain of the ZIKV, MR766, serially passaged in monkey and mosquito cells efficiently infects human neural progenitor cells (hNPCs) derived from induced pluripotent stem cells. Infected hNPCs further release infectious ZIKV particles. Importantly, ZIKV infection increases cell death and dysregulates cell-cycle progression, resulting in attenuated hNPC growth. Global gene expression analysis of infected hNPCs reveals transcriptional dysregulation, notably of cell-cycle-related pathways. Our results identify hNPCs as a direct ZIKV target. In addition, we establish a tractable experimental model system to investigate the impact and mechanism of ZIKV on human brain development and provide a platform to screen therapeutic compounds.

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