Zika Disrupts Neural Progenitor Development - Mice Microcephaly - Cell ST

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

http://www.cell.com/cell-stem-cell/pdfExtended/S1934-5909(16)30084-4

 

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Cui Li,1,2,7 Dan Xu,5,7 Qing Ye,3,7 Shuai Hong,1,2,7 Yisheng Jiang,1 Xinyi Liu,1,2 Nana Zhang,3,6 Lei Shi,1 Cheng-Feng Qin,3, * and Zhiheng Xu1,4, *

1State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China

2University of Chinese Academy of Sciences, Beijing 100101, China

3Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China

4Parkinson’s Disease Center, Beijing Institute for Brain Disorders, Beijing 100101, China

5Institute of Life Sciences, Fuzhou University, Fuzhou 350116, China

6Guangxi Medical University, Nanning 530021, China

7Co-first author

*Correspondence: [email protected] (C.-F.Q.), [email protected] (Z.X.)

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In Brief

The suspected link between Zika virus (ZIKV) infection and microcephaly has raised urgent global alarm. However, there is so far no direct evidence for ZIKV infection impacting brain development. In this study, Li, Xu, and colleagues show that ZIKV replicates efficiently in the mouse embryonic brain by mainly targeting neural progenitor cells. They also show that infected brains are smaller with enlarged ventricles and a thinner cortex, consistent with a microcephalic phenotype.

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Highlights

Zika virus (ZIKV) replicates very efficiently in embryonic mouse brain

ZIKV infects neural progenitor cells (NPCs) and causes microcephaly

ZIKV infection leads to NPC cell-cycle arrest and defects in differentiation

ZIKV infection induces immune response in brain and apoptosis of post-mitotic neurons

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SUMMARY

The link between Zika virus (ZIKV) infection and microcephaly has raised urgent global alarm. The historical African ZIKV MR766 was recently shown to infect cultured human neural precursor cells (NPCs), but unlike the contemporary ZIKV strains, it is not believed to cause microcephaly. Here we investigated whether the Asian ZIKV strain SZ01 could infect NPCs in vivo and affect brain development. We found that SZ01 replicates efficiently in embryonic mouse brain by directly targeting different neuronal linages. ZIKV infection leads to cell-cycle arrest, apoptosis, and inhibition of NPC differentiation, resulting in cortical thinning and microcephaly. Global gene expression analysis of infected brains reveals upregulation of candidate flavirus entry receptors and dysregulation of genes associated with immune response, apoptosis, and microcephaly. Our model provides evidence for a direct link between Zika virus infection and microcepahly, with potential for further exploration of the underlying mechanisms.

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INTRODUCTION

Recent world attention has been drawn to a global Zika virus (ZIKV) outbreak and its link with devastating cases of microcephaly. ZIKV infection is spreading rapidly within the Americas after originating from an outbreak in Brazil. So far 31 countries and territories in South and Central America have reported the circulation of this type of mosquito-borne flavivirus (Heukelbach et al., 2016). There is mounting concern about the association of ZIKV infection with approximately 5,000 fetal and newborn microcephaly cases and with serious neurological complications in adults, such as Guillain-Barre´ syndrome. In November 2015, the Brazilian Ministry of Health reported a 20-fold increase in cases of neonatal microcephaly, which corresponds geographically and temporally to the ZIKV outbreak (Marrs et al., 2016). Due to this global threat, WHO declared a public health emergency of international concern on February 1 (Heymann et al., 2016; Marrs et al., 2016).

Precise timing of proliferation/self-renewal of neural progenitor cells (NPCs) and of their differentiation, neuronal migration, and maturation are essential for normal mammalian brain development. Disturbance of these processes leads to developmental brain disorders including microcephaly (Kriegstein and AlvarezBuylla, 2009; Manzini and Walsh, 2011; Nowakowski et al., 2016; Thornton and Woods, 2009).

A causal association between ZIKV infection and microcephaly was proposed based on an increased incidence of microcephaly coinciding with the ZIKV outbreak and the detection of ZIKV in both microcephalic fetal brain tissues and the amniotic fluid of pregnant women with microcephalic fetuses (Calvet et al., 2016; Driggers et al., 2016; Marrs et al., 2016; Mlakar et al., 2016). In addition, ZIKV strain MR766 has been shown to be capable of infecting NPCs derived from human induced pluripotent stem cells (hiPSCs) (Tang et al., 2016). ZIKV infection induces cell death and deregulation of cell-cycle progression of hiPSCs, reducing their viability and growth as neurospheres and brain organoids (Garcez et al., 2016; Tang et al., 2016, Qian et al., 2016). However, there is still an urgent demand for direct evidence from mammalian animal models that ZIKV infection can cause microcephaly. Here we used an Asian ZIKV strain, SZ01, isolated from a patient infected in Samoa (Deng et al., 2016) to investigate whether ZIKV infects the embryonic mouse brain and affects brain development.

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