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.

Genetic diversity of Collaborative Cross mice controls viral replication, clinical severity and brain pathology induced by Zika virus infection, independently of Oas1b

“…Although the kinetics of viral replication were different between cell types, with a swift drop in CC001 macrophages at 48h while it was slower in CC001 MEFs and primary neurons, replication steadily increased over time in all three cell types of CC071 origin, leading to significantly higher viral titers at 72h. Our data is consistent with the observation by Caires-Junior et al who reported increased ZIKV replication rate in iPS-derived neuroprogenitor cells from CZS-affected babies compared with their unaffected dizygotic twin (13). Therefore, our results strongly suggest that increased replication rate in CC071 compared with CC001 likely contributes to its higher plasma and brain viral loads and to its higher overall susceptibility to ZIKV.…”

“…ZIKV is a serious public health concern considering the occurrence of severe neurological complications in adults and congenital malformations that can result from the infection of pregnant women. The variable outcomes of ZIKV infection in humans has led to hypothesize a role for host genetic factors (9, 13) although this has never been demonstrated thus far. As for other infectious diseases, human genetic studies on susceptibility to ZIKV would require large cohorts of patients and would be confounded by pathogen genetics, pathogen dose, mosquito-dependent factors and multiple environmental parameters.…”

“…Recent evidence indicates that the regulation of innate immunity genes is driven by host genetic background in human fetal brain-derived neural stem cells (hNSCs) infected in vitro with ZIKV (12). Additionally, the analysis of pairs of dizygotic twins exposed to ZIKV during pregnancy and discordant for CZS suggests multigenic host susceptibility to ZIKV-induced brain malformations (13).…”

The pyriproxyfen metabolite 4'OH- pyriproxyfen disrupts thyroid hormone signaling and enhances Musashi-1 levels in neuroprogenitors.

“…potential TR binding sites (Chang and Pan, 1998; Paquette et al, 2014; Quack et al, 2002). A recent study compared neuroprogenitor cells (NPCs) from twins discordant for Congenital Zika Syndrome (CZS) displayed differences in NPC gene expression that could underly increased susceptibility to ZIKV-induced microcephaly through viral replication (Caires-Júnior et al, 2018).…”

Congenital Zika Syndrome is associated with interferon alfa receptor 1

“…One important risk factor for CSZ is infection within the first trimester of pregnancy, which poses almost twice as high risks of severe outcomes as CNS abnormalities when compared with the third trimester infections (Brasil et al, 2016). It has been reported that genetic background can influence the outcome, although no targets or candidates have been identified, and it is likely that mothers' genetic factors could also be involved in CZS outcome (Caires-Júnior et al, 2018).…”