Inhibition of innate immune response ameliorates Zika virus-induced neurogenesis deficit in human neural stem cells.

Pei Xu,Scott C Weaver,Pei-Yong Shi,Alexander N Freiberg,Xuping Xie,Amulya Sajja,Jing Zou,Hongjie Xia,Ping Wu,Tiffany J Dunn,Yongjia Yu,Nikos Vasilakis,Chao Shan,Beatriz H Thames,Junling Gao,Gregory Gromowski

doi:10.1371/journal.pntd.0009183

Pei Xu, Scott C Weaver + Show 14 more

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https://doi.org/10.1371/journal.pntd.0009183

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Abstract

Global Zika virus (ZIKV) outbreaks and their strong link to microcephaly have raised major public health concerns. ZIKV has been reported to affect the innate immune responses in neural stem/progenitor cells (NS/PCs). However, it is unclear how these immune factors affect neurogenesis. In this study, we used Asian-American lineage ZIKV strain PRVABC59 to infect primary human NS/PCs originally derived from fetal brains. We found that ZIKV overactivated key molecules in the innate immune pathways to impair neurogenesis in a cell stage-dependent manner. Inhibiting the overactivated innate immune responses ameliorated ZIKV-induced neurogenesis reduction. This study thus suggests that orchestrating the host innate immune responses in NS/PCs after ZIKV infection could be promising therapeutic approach to attenuate ZIKV-associated neuropathology.

Highlights

Zika virus (ZIKV) outbreaks and their strong link to microcephaly and other congenital abnormalities have raised public health concerns globally [1,2,3,4,5]
We found that inhibiting the overactivated innate immune responses ameliorated Zika virusinduced neurogenesis reduction in human neural stem cells, which are the origin of the brain
This study suggests that coordinating the host innate immune responses in neural stem cells after ZIKV infection could be promising therapeutic approach to attenuate ZIKV-associated neuropathology

Summary

Introduction

Zika virus (ZIKV) outbreaks and their strong link to microcephaly and other congenital abnormalities have raised public health concerns globally [1,2,3,4,5]. ZIKV-associated microcephaly occurs most likely due to the high susceptibility of neural stem/progenitor cells (NS/PCs), which populate and develop the fetal brain, to ZIKV infection [12,13,14,15]. Ferraris et al [19] have shown that ZIKV induces higher viral production and cytotoxic effects in undifferentiated hNPCs compared to differentiated cells. It is not clear how these differential responses to ZIKV affect neurogenesis during the neurodevelopmental process, and what is the underlying mechanism

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