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

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.

SUBMITTER: Caires-Junior LC

PROVIDER: S-EPMC5797251 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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

Caires-Júnior Luiz Carlos LC Goulart Ernesto E Melo Uirá Souto US Araujo Bruno Henrique Silva BHS Alvizi Lucas L Soares-Schanoski Alessandra A de Oliveira Danyllo Felipe DF Kobayashi Gerson Shigeru GS Griesi-Oliveira Karina K Musso Camila Manso CM Amaral Murilo Sena MS daSilva Lucas Ferreira LF Astray Renato Mancini RM Suárez-Patiño Sandra Fernanda SF Ventini Daniella Cristina DC Gomes da Silva Sérgio S Yamamoto Guilherme Lopes GL Ezquina Suzana S Naslavsky Michel Satya MS Telles-Silva Kayque Alves KA Weinmann Karina K van der Linden Vanessa V van der Linden Helio H de Oliveira João Ricardo Mendes JRM Arrais Nivia Maria Rodrigues NMR Melo Adriana A Figueiredo Thalita T Santos Silvana S Meira Joanna Goes Castro JGC Passos Saulo Duarte SD de Almeida Roque Pacheco RP Bispo Ana Jovina Barreto AJB Cavalheiro Esper Abrão EA Kalil Jorge J Cunha-Neto Edécio E Nakaya Helder H Andreata-Santos Robert R de Souza Ferreira Luis Carlos LC Verjovski-Almeida Sergio S Ho Paulo Lee PL Passos-Bueno Maria Rita MR Zatz Mayana M

Nature communications 20180202 1

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 infec ...[more]

PMID: 29396410

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Project description:Zika virus (ZIKV) causes congenital Zika syndrome (CZS), which is characterized by fetal demise, microcephaly and other abnormalities. ZIKV in the pregnant woman circulation must cross the placental barrier that includes fetal endothelial cells and trophoblasts, in order to reach the fetus. CZS occurs in ~1-40% of cases of pregnant women infected by ZIKV, suggesting that mothers' infection by ZIKV during pregnancy is not deterministic for CZS phenotype in the fetus. Therefore, other susceptibility factors might be involved, including the host genetic background. We have previously shown that in three pairs of dizygotic twins discordant for CZS, neural progenitor cells (NPCs) from the CZS-affected twins presented differential in vitro ZIKV susceptibility compared with NPCs from the non-affected. Here, we analyzed human-induced-pluripotent-stem-cell-derived (hiPSC-derived) trophoblasts from these twins and compared by RNA-Seq the trophoblasts from CZS-affected and non-affected twins. Following in vitro exposure to a Brazilian ZIKV strain (ZIKVBR), trophoblasts from CZS-affected twins were significantly more susceptible to ZIKVBR infection when compared with trophoblasts from the non-affected. Transcriptome profiling revealed no differences in gene expression levels of ZIKV candidate attachment factors, IFN receptors and IFN in the trophoblasts, either before or after ZIKVBR infection. Most importantly, ZIKVBR infection caused, only in the trophoblasts from CZS-affected twins, the downregulation of genes related to extracellular matrix organization and to leukocyte activation, which are important for trophoblast adhesion and immune response activation. In addition, only trophoblasts from non-affected twins secreted significantly increased amounts of chemokines RANTES/CCL5 and IP10 after infection with ZIKVBR. Overall, our results showed that trophoblasts from non-affected twins have the ability to more efficiently activate genes that are known to play important roles in cell adhesion and in triggering the immune response to ZIKV infection in the placenta, and this may contribute to predict protection from ZIKV dissemination into fetuses' tissues.

Dataset Information

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

Publications

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

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