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Updated: May 5, 2026
Modelling Zika Virus Infection of the Developing Human Brain In Vitro Using Stem Cell Derived Cerebral Organoids
Published on: September 19, 2017
A single mutation in the prM protein of Zika virus contributes to fetal microcephaly
Ling Yuan1,2, Xing-Yao Huang3, Zhong-Yu Liu3
1State Key Laboratory of Molecular Developmental Biology, Chinese Academy of Sciences (CAS) Center for Excellence in Brain Science and Intelligence Technology, Institute of Genetics and Developmental Biology, CAS, Beijing 100101, China.
Abstract:
Zika virus (ZIKV) has evolved into a global health threat because of its unexpected causal link to microcephaly. Phylogenetic analysis reveals that contemporary epidemic strains have accumulated multiple substitutions from their Asian ancestor. Here we show that a single serine-to-asparagine substitution [Ser139→Asn139 (S139N)] in the viral polyprotein substantially increased ZIKV infectivity in both human and mouse neural progenitor cells (NPCs) and led to more severe microcephaly in the mouse fetus, as well as higher mortality rates in neonatal mice. Evolutionary analysis indicates that the S139N substitution arose before the 2013 outbreak in French Polynesia and has been stably maintained during subsequent spread to the Americas. This functional adaption makes ZIKV more virulent to human NPCs, thus contributing to the increased incidence of microcephaly in recent ZIKV epidemics.
Insights
A specific Zika virus (ZIKV) mutation, Ser139Asn, significantly enhances infectivity in neural progenitor cells. This adaptation is linked to increased microcephaly severity and mortality in mouse models, explaining epidemic virulence.
Area of Science:
- Virology
- Neuroscience
- Genetics
Background:
- Zika virus (ZIKV) emerged as a global health concern due to its link to microcephaly.
- Epidemic ZIKV strains show genetic divergence from ancestral Asian strains.
Purpose of the Study:
- To investigate the impact of specific genetic mutations on ZIKV infectivity and pathogenicity.
- To understand the evolutionary basis of increased ZIKV virulence.
Main Methods:
- Phylogenetic analysis of ZIKV strains.
- Functional assays using human and mouse neural progenitor cells (NPCs).
- In vivo studies using mouse models for microcephaly and mortality.
Main Results:
- A single amino acid substitution (Ser139Asn) in the ZIKV polyprotein significantly increased infectivity in human and mouse NPCs.
- The Ser139Asn mutation led to more severe microcephaly in fetal mice and increased mortality in neonates.
- Evolutionary analysis confirmed the S139N substitution predates the 2013 outbreak and was maintained during epidemic spread.
Conclusions:
- The Ser139Asn substitution is a key functional adaptation enhancing ZIKV virulence against neural progenitor cells.
- This mutation likely contributed to the increased incidence of microcephaly during recent ZIKV epidemics.
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