Discordant congenital Zika syndrome twins show differential in vitro viral susceptibility of neural progenitor cells.
Luiz Carlos Caires-JúniorErnesto GoulartUirá Souto MeloBruno Henrique Silva AraujoLucas AlviziAlessandra Soares-SchanoskiDanyllo Felipe de OliveiraGerson Shigeru KobayashiKarina Griesi-OliveiraCamila Manso MussoMurilo Sena AmaralLucas Ferreira daSilvaRenato Mancini AstraySandra Fernanda Suárez-PatiñoDaniella Cristina VentiniSérgio Gomes da SilvaGuilherme Lopes YamamotoSuzana EzquinaMichel Satya NaslavskyKayque Alves Telles-SilvaKarina WeinmannVanessa van der LindenHelio van der LindenJoão Ricardo Mendes de OliveiraNivia Maria Rodrigues ArraisAdriana MeloThalita FigueiredoSilvana SantosJoanna Goes Castro MeiraSaulo Duarte PassosRoque Pacheco de AlmeidaAna Jovina Barreto BispoEsper Abrão CavalheiroJorge KalilEdécio Cunha-NetoHelder Takashi Imoto NakayaRobert Andreata-SantosLuis Carlos de Souza FerreiraSergio Verjovski-AlmeidaPaulo Lee HoMaria Rita Passos-BuenoMayana ZatzPublished in: Nature communications (2018)
Congenital Zika syndrome (CZS) causes early brain development impairment by affecting neural progenitor cells (NPCs). Here, we analyze NPCs from three pairs of dizygotic twins discordant for CZS. We compare by RNA-Seq the NPCs derived from CZS-affected and CZS-unaffected twins. Prior to Zika virus (ZIKV) infection the NPCs from CZS babies show a significantly different gene expression signature of mTOR and Wnt pathway regulators, key to a neurodevelopmental program. Following ZIKV in vitro infection, cells from affected individuals have significantly higher ZIKV replication and reduced cell growth. Whole-exome analysis in 18 affected CZS babies as compared to 5 unaffected twins and 609 controls excludes a monogenic model to explain resistance or increased susceptibility to CZS development. Overall, our results indicate that CZS is not a stochastic event and depends on NPC intrinsic susceptibility, possibly related to oligogenic and/or epigenetic mechanisms.