Chapter 16 - Host genetic susceptibility to ZIKV congenital syndrome: A tale of twins

Abstract

Zika virus (ZIKV) is a skillful neural progenitor cell (NPC) pathogen. The association between ZIKV during pregnancy and the birth of babies with severe microcephaly caused by NPC impairment (i.e., congenital Zika syndrome or CZS) called the world’s attention. Although each case is a tragedy, it was intriguing that less than 10% of babies exposed to ZIKV during pregnancy were affected during the 2015–2016 ZIKV outbreak in Brazil. Aiming to enhance our comprehension of the underlying mechanisms and to understand the role of host genetic background causing ZIKV neuronal pathology, we focused our investigation in pairs of twins. We ascertained nine pairs and obtained samples from eight. Among them, six pairs were dizygotic (DZ) and two were monozygotic (MZ). The two MZ were both affected, but five of the six DZ were discordant (i.e., one affected and the other normal) for CZS. Through a gigantic effort, we were able to obtain blood samples in conditions which allowed deriving induced pluripotent stem cells (iPS) and NPCs from three pairs of discordant twins. These six NPCs samples were then infected in vitro with ZIKV. Surprisingly, the results clearly indicate that affected babies’ cells were much more efficient in replicating ZIKV once infected, thereby developing associated severe cellular pathology. RNA sequencing (RNA-Seq) highlighted a differential neurodevelopmental program that involves Wnt and mTOR signaling. Further analysis showed that mTOR was one of the main drivers of the discordancy observed in the twins’ cohort. Overall, our results indicate that CZS is not a stochastic event and depends on NPC intrinsic susceptibility, possibly related to epigenetic and/or oligogenic mechanisms. This pioneering study sheds light on the ZIKV molecular infection mechanism and how genetics can enhance our understanding of clinically relevant findings and individual-specific response to pathogens.