ZIKA virus elicits P53 activation and genotoxic stress in human neural progenitors similar to mutations involved in severe forms of genetic microcephaly.

Vincent El Ghouzzi,Gaia E Berto,Federico T Bianchi,Marco Vignuzzi,Ferdinando Di Cunto,Sophie Lebon,Alessandra Ma Chiotto,Francesco Sgrò,Pierre Gressens,Malgorzata Rak,Marta Gai,Chiara Tocco,Gianmarco Pallavicini,Sandrine Passemard,Laetitia Aubry,Ivan Molineris,Etienne Simon-Loriere,Bryan C Mounce

doi:10.1038/cddis.2016.266

Abstract

Epidemiological evidence from the current outbreak of Zika virus (ZIKV) and recent studies in animal models indicate a strong causal link between ZIKV and microcephaly. ZIKV infection induces cell-cycle arrest and apoptosis in proliferating neural progenitors. However, the mechanisms leading to these phenotypes are still largely obscure. In this report, we explored the possible similarities between transcriptional responses induced by ZIKV in human neural progenitors and those elicited by three different genetic mutations leading to severe forms of microcephaly in mice. We found that the strongest similarity between all these conditions is the activation of common P53 downstream genes. In agreement with these observations, we report that ZIKV infection increases total P53 levels and nuclear accumulation, as well as P53 Ser15 phosphorylation, correlated with genotoxic stress and apoptosis induction. Interestingly, increased P53 activation and apoptosis are induced not only in cells expressing high levels of viral antigens but also in cells showing low or undetectable levels of the same proteins. These results indicate that P53 activation is an early and specific event in ZIKV-infected cells, which could result from cell-autonomous and/or non-cell-autonomous mechanisms. Moreover, we highlight a small group of P53 effector proteins that could act as critical mediators, not only in ZIKV-induced microcephaly but also in many genetic microcephaly syndromes.

Highlights

ZIKA virus elicits P53 activation and genotoxic stress in human neural progenitors similar to mutations involved in severe forms of genetic microcephaly and p53
We explored this possibility, by comparing the gene expression profile of induced pluripotent stem cellderived human neural progenitors cells infected with Zika virus (ZIKV),[12] with the profiles of developing neural tissues obtained from three different mouse models of severe genetic microcephaly
Gene Ontology (GO) analysis of upregulated genes displayed enrichment of proteins involved in transcription, protein transport and catabolic processes, together with increased expression levels of genes involved in the regulation of

Summary

Introduction

ZIKA virus elicits P53 activation and genotoxic stress in human neural progenitors similar to mutations involved in severe forms of genetic microcephaly and p53. Genetic and environmental conditions that affect the normal expansion of neuronal progenitors, the timing of their differentiation and the survival of their progeny may severely reduce the final number of brain cells, resulting in microcephaly. A distinct possibility to explain the specificity of these phenotypes is that ZIKV infection may directly or indirectly affect some of the molecular mechanisms that are implicated in the pathogenesis of genetic CM.[4,7,23] In this report, we explored this possibility, by comparing the gene expression profile of induced pluripotent stem cell (iPSC)derived human neural progenitors cells (hNPCs) infected with ZIKV,[12] with the profiles of developing neural tissues obtained from three different mouse models of severe genetic microcephaly.

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Conclusion