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Discordant congenital Zika syndrome twins show differential in vitro viral susceptibility of neural progenitor cells

2018; Nature Portfolio; Volume: 9; Issue: 1 Linguagem: Inglês

10.1038/s41467-017-02790-9

2041-1723

Luiz C. Caires-Júnior, Ernesto Goulart, Uirá Souto Melo, Bruno Henrique Silva Araújo, Lucas Alvizi, Alessandra Soares‐Schanoski, Danyllo Oliveira, Gerson Shigeru Kobayashi, Karina Griesi‐Oliveira, Camila Manso Musso, Murilo Sena Amaral, Lucas F. daSilva, Renato Mancini Astray, Sandra Fernanda Suárez-Patiño, Daniella C. Ventini, Sérgio Gomes da Silva, Guilherme Lopes Yamamoto, Suzana Ezquina, Michel Satya Naslavsky, Kayque A. Telles-Silva, Karina Weinmann, Vanessa van der Linden, Hélio van der Linden, João Ricardo Mendes de Oliveira, Nívia Maria Rodrigues Arrais, Adriana Suely de Oliveira Melo, Thalita Figueiredo, Silvana Santos, Joanna Góes Castro Meira, Saulo Duarte Passos, Roque Pacheco de Almeida, Ana Jovina Barreto Bispo, Ésper A. Cavalheiro, Jorge Kalil, Edécio Cunha‐Neto, Helder I. Nakaya, Robert Andreata‐Santos, Luís Carlos de Souza Ferreira, Sergio Verjovski‐Almeida, Paulo Lee Ho, Maria Rita Passos‐Bueno, Mayana Zatz,

Viral Infections and Vectors

Abstract 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.