title: ZIKA virus elicits P53 activation and genotoxic stress in human neural progenitors similar to mutations involved in severe forms of genetic microcephaly.
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.
authors: PROTECT, INSERM, Unversité Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors: Vincent El
authors: VE
authors: Ghouzzi
authors: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Centre, University of Turin, Turin, Italy.
authors: Federico T
authors: FT
authors: Bianchi
authors: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Centre, University of Turin, Turin, Italy.
authors: Ivan
authors: I
authors: Molineris
authors: Institut Pasteur, Centre National de la RechercheScientifique UMR 3569, Viral Populations and Pathogenesis Unit, Paris, France.
authors: Bryan C
authors: BC
authors: Mounce
authors: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Centre, University of Turin, Turin, Italy.
authors: Gaia E
authors: GE
authors: Berto
authors: PROTECT, INSERM, Unversité Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors: Malgorzata
authors: M
authors: Rak
authors: PROTECT, INSERM, Unversité Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors: Sophie
authors: S
authors: Lebon
authors: UEVE UMR 861, I-Stem, AFM, Evry, France.
authors: Laetitia
authors: L
authors: Aubry
authors: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Centre, University of Turin, Turin, Italy.
authors: Chiara
authors: C
authors: Tocco
authors: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Centre, University of Turin, Turin, Italy.
authors: Marta
authors: M
authors: Gai
authors: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Centre, University of Turin, Turin, Italy.
authors: Alessandra Ma
authors: AM
authors: Chiotto
authors: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Centre, University of Turin, Turin, Italy.
authors: Francesco
authors: F
authors: Sgrò
authors: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Centre, University of Turin, Turin, Italy.
authors: Gianmarco
authors: G
authors: Pallavicini
authors: Institut Pasteur, Functional Genetics of Infectious Diseases Unit, Paris 75724, France.|CNRS URA3012, Paris 75015, France.
authors: Etienne
authors: E
authors: Simon-Loriere
authors: PROTECT, INSERM, Unversité Paris Diderot, Sorbonne Paris Cité, Paris, France.|Département de Génétique, Hôpital Robert Debré, Paris, France.
authors: Sandrine
authors: S
authors: Passemard
authors: Institut Pasteur, Centre National de la RechercheScientifique UMR 3569, Viral Populations and Pathogenesis Unit, Paris, France.
authors: Marco
authors: M
authors: Vignuzzi
authors: PROTECT, INSERM, Unversité Paris Diderot, Sorbonne Paris Cité, Paris, France.|Center for Developing Brain, King' s College, London, UK.
authors: Pierre
authors: P
authors: Gressens
authors: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Centre, University of Turin, Turin, Italy.|Neuroscience Institute of Turin, Turin, Italy.
authors: Ferdinando
authors: F
authors: Di Cunto
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D004249:DNA Damage / Q000235:genetics*; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D008831:Microcephaly / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D058953:Neural Stem Cells / Q000378:metabolism* / Q000821:virology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics; D000071244:Zika Virus / Q000502:physiology*; D000071243:Zika Virus Infection / Q000235:genetics / Q000473:pathology / Q000821:virology
chemical_list: D016159:Tumor Suppressor Protein p53