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Stress-induced unfolded protein response contributes to Zika virus–associated microcephaly.

Ivan Gladwyn-Ng 1 Lluís Cordón-Barris 1 Christian Alfano 1 Catherine Creppe 1 Thérèse Couderc 2 Giovanni Morelli 1, 3 Nicolas Thelen 1 Michelle America 1 Bettina Bessières 4, 5 Ferechte Encha-Razavi 4 Maryse Bonniere 4 Ikuo Suzuki 6 Marie Flamand 7 Pierre Vanderhaeghen 6, 8 Marc Thiry 1 Marc Lecuit 2, 9, 10 Laurent Nguyen 1
1 GIGA-Neurosciences, Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R) [Liège]
2 Biologie des Infections - Biology of Infection
3 BIOMED [Hasselt]
4 Département d’Histologie-Embryologie-Cytogénétique
5 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
6 IRIBHM - Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire
7 Virologie Structurale
8 WELBIO - Walloon Excellence in Life sciences and BIOtechnology [Liège]
9 UPD5 - Université Paris Descartes - Paris 5
10 CHU Necker - Enfants Malades [AP-HP]
Abstract : Accumulating evidence support a causal link between Zika virus (ZIKV) infection during gestation and congenital microcephaly. However, the mechanism of ZIKV-associated microcephaly remains unclear. We combined analyses of ZIKV-infected human fetuses, cultured human neural stem cells and mouse embryos to understand how ZIKV induces microcephaly. We show that ZIKV triggers endoplasmic reticulum stress and unfolded protein response in the cerebral cortex of infected postmortem human fetuses as well as in cultured human neural stem cells. After intracerebral and intraplacental inoculation of ZIKV in mouse embryos, we show that it triggers endoplasmic reticulum stress in embryonic brains in vivo. This perturbs a physiological unfolded protein response within cortical progenitors that controls neurogenesis. Thus, ZIKV-infected progenitors generate fewer projection neurons that eventually settle in the cerebral cortex, whereupon sustained endoplasmic reticulum stress leads to apoptosis. Furthermore, we demonstrate that administration of pharmacological inhibitors of unfolded protein response counteracts these pathophysiological mechanisms and prevents microcephaly in ZIKV-infected mouse embryos. Such defects are specific to ZIKV, as they are not observed upon intraplacental injection of other related flaviviruses in mice.
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Submitted on : Thursday, March 22, 2018 - 5:23:06 PM
Last modification on : Wednesday, October 20, 2021 - 2:59:02 AM

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PASTEUR | UNIV-PARIS5 | USPC | UNIV-PARIS | UP-SANTE

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Ivan Gladwyn-Ng, Lluís Cordón-Barris, Christian Alfano, Catherine Creppe, Thérèse Couderc, et al.. Stress-induced unfolded protein response contributes to Zika virus–associated microcephaly.. Nature Neuroscience, Nature Publishing Group, 2018, 21 (1), pp.63-71. ⟨10.1038/s41593-017-0038-4⟩. ⟨pasteur-01741181⟩

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