Zika Virus Disrupts Neural Progenitor Development and Leads to Microcephaly in Mice

Li, Cui; Xu, Dan; Ye, Qing; Hong, Shuai; Jiang, Yisheng; Liu, Xinyi; Zhang, Nana; Shi, Lei; Qin, Cheng‐Feng; Xu, Zhiheng

doi:10.1016/j.stem.2016.10.017

Cited by 272 publications

(367 citation statements)

References 0 publications

Supporting

Mentioning

338

Contrasting

Unclassified

Order By: Relevance

“…Li and col. [309] demonstrated that ZIKV infects mainly progenitor cells in the mouse, leading to smaller brain sizes 5 days after the infection (E18.5), cell-cycle dysregulation, neural progenitor cell (NPC) defects in differentiation and increased active caspase-3 positive cells. Moreover, ZIKV infects human NPCs derived from iPSCs, increases cell death and deregulates cell-cycle progression, resulting in attenuated hNPC growth [297].…”

Section: Non-genetic Origins Of Mcds (Illustrated By Zika Virus Infecmentioning

confidence: 99%

Genetics and mechanisms leading to human cortical malformations

Romero

Bahi‐Buisson

Francis

2018

Seminars in Cell & Developmental Biology

105

View full text Add to dashboard Cite

Section: Non-genetic Origins Of Mcds (Illustrated By Zika Virus Infecmentioning

confidence: 99%

Genetics and mechanisms leading to human cortical malformations

Romero

Bahi‐Buisson

Francis

2018

Seminars in Cell & Developmental Biology

105

View full text Add to dashboard Cite

“…In mouse models, strains from the African and Asian lineages were able to establish infection (27)(28)(29)(30). Studies with pregnant animals focused on the strains recently isolated from the Americas or French Polynesia, which were able to cause development problems mimicking the microcephaly observed in humans (15,20,21,31,32). Additionally, ZIKV strains isolated from Brazil and injected into nonhuman primates at high dosages were able to cause alterations in the fetal brain (19).…”

mentioning

confidence: 99%

Suppression of Zika Virus Infection and Replication in Endothelial Cells and Astrocytes by PKA Inhibitor PKI 14-22

Cheng

Silva

Huang

et al. 2018

J Virol

View full text Add to dashboard Cite

The recent outbreak of Zika virus (ZIKV), a reemerging flavivirus, and its associated neurological disorders, such as Guillain-Barré (GB) syndrome and microcephaly, have generated an urgent need to develop effective ZIKV vaccines and therapeutic agents. Here, we used human endothelial cells and astrocytes, both of which represent key cell types for ZIKV infection, to identify potential inhibitors of ZIKV replication. Because several pathways, including the AMP-activated protein kinase (AMPK), protein kinase A (PKA), and mitogen-activated protein kinase (MAPK) signaling pathways, have been reported to play important roles in flavivirus replication, we tested inhibitors and agonists of these pathways for their effects on ZIKV replication. We identified the PKA inhibitor PKI 14-22 (PKI) to be a potent inhibitor of ZIKV replication. PKI effectively suppressed the replication of ZIKV from both the African and Asian/American lineages with a high efficiency and minimal cytotoxicity. While ZIKV infection does not induce PKA activation, endogenous PKA activity is essential for supporting ZIKV replication. Interestingly, in addition to PKA, PKI also inhibited another unknown target(s) to block ZIKV replication. PKI inhibited ZIKV replication at the postentry stage by preferentially affecting negative-sense RNA synthesis as well as viral protein translation. Together, these results have identified a potential inhibitor of ZIKV replication which could be further explored for future therapeutic application.IMPORTANCE There is an urgent need to develop effective vaccines and therapeutic agents against Zika virus (ZIKV) infection, a reemerging flavivirus associated with neurological disorders, including Guillain-Barré (GB) syndrome and microcephaly. By screening for inhibitors of several cellular pathways, we have identified the PKA inhibitor PKI 14-22 (PKI) to be a potent inhibitor of ZIKV replication. We show that PKI effectively suppresses the replication of all ZIKV strains tested with minimal cytotoxicity to human endothelial cells and astrocytes, two key cell types for ZIKV infection. Furthermore, we show that PKI inhibits ZIKV negative-sense RNA synthesis and viral protein translation. This study has identified a potent inhibitor of ZIKV infection which could be further explored for future therapeutic application.

show abstract

“…Zika virus infection leads to an alteration in the regulation of genes associated with the immune response, cell cycle, differentiation, and apoptosis in NPCs, resulting in neurological malformations [63]. Furthermore, Tang et al [64] demonstrated that Zika virus can also infect human (h) NPCs in the cell culture system.…”

Section: Possible Molecular Events Leading To Microcephalymentioning

confidence: 99%

Zika Virus-Induced Microcephaly and Its Possible Molecular Mechanism

et al. 2016

View full text Add to dashboard Cite

Zika virus is an arthropod-borne re-emerging pathogen associated with the global pandemic of 2015-2016. The devastating effect of Zika viral infection is reflected by its neurological manifestations such as microcephaly in newborns. This scenario evoked our interest to uncover the neurotropic localization, multiplication of the virus, and the mechanism of microcephaly. The present report provides an overview of a possible molecular mechanism of Zika virus-induced microcephaly based on recent publications. Transplacental transmission of Zika viral infection from mother to foetus during the first trimester of pregnancy results in propagation of the virus in human neural progenitor cells (hNPCs), where entry is facilitated by the receptor (AXL protein) leading to the alteration of signalling and immune pathways in host cells. Further modification of the viral-induced TLR3-mediated immune network in the infected hNPCs affects viral replication. Downregulation of neurogenesis and upregulation of apoptosis in hNPCs leads to cell cycle arrest and death of the developing neurons. In addition, it is likely that the environmental, physiological, immunological, and genetic factors that determine in utero transmission of Zika virus are also involved in neurotropism. Despite the global concern regarding the Zika-mediated epidemic, the precise molecular mechanism of neuropathogenesis remains elusive.

show abstract

Zika Virus Disrupts Neural Progenitor Development and Leads to Microcephaly in Mice

Cited by 272 publications

References 0 publications

Genetics and mechanisms leading to human cortical malformations

Genetics and mechanisms leading to human cortical malformations

Suppression of Zika Virus Infection and Replication in Endothelial Cells and Astrocytes by PKA Inhibitor PKI 14-22

Zika Virus-Induced Microcephaly and Its Possible Molecular Mechanism

Contact Info

Product

Resources

About