Molecular Mechanisms of ZIKV-Induced Teratogenesis: A Systematic Review of Studies in Animal Models

Abstract

Zika virus (ZIKV) is a teratogen that causes congenital anomalies, being linked to microcephaly in children exposed during pregnancy. Animal studies have been conducted to investigate the molecular mechanisms related to ZIKV teratogenesis. Although animal models can mimic the effects of ZIKV in human embryo development, few in vivo studies have addressed molecular changes following ZIKV infection in embryos. Moreover, few literature reviews have been conducted with these studies. The aim of this systematic review is to evaluate the molecular mechanisms of ZIKV teratogenesis determined from studies in animal models. PubMed/MEDLINE, EMBASE, Web of Science, and Scopus as well as grey literature were searched for studies that evaluated molecular alterations related to ZIKV teratogenesis which occurred during embryonic development. Nine studies were included: six with mice, one with mice and guinea pigs, one with pigs and one with chickens. In general, studies presented an unclear or high risk of bias for methodological criteria. Most of studies reported embryos exposed to ZIKV presenting microcephaly, reduced cortex thickness, and growth restriction. Different techniques were used to evaluated molecular changes in the animals following ZIKV infection: RNA sequencing, RT-qPCR, and in situ hybridization. It was found that common pathways are changed in most studies, being pathways related to immune response upregulated and those involved to neurodevelopment downregulated.

Keywords: Congenital Zika syndrome; Congenital abnormalities; Embryo; Gene expression; Molecular pathway; Molecular techniques; Nervous system development; Zika virus infection.

Fig. 1

Flow chart showing the search and screening strategy to identify publications eligible for investigating molecular mechanism of ZIKV teratogenesis from animal studies

Fig. 2

Genes with a differential gene expression, according to the authors, in the three studies that performed the transcriptome analysis to assess the gene expression after ZIKV exposure (all upregulated). A Veen diagram highlighting the number of statistically significant differentially expressed genes after ZIKV exposure, according to the authors of each study, shared between the three studies; B enrichment analyses of gene ontologies related to these differentially expressed genes shared in all studies that performed the transcriptome analysis

Fig. 3

Risk of bias of the studies included in this systematic review. The proportion of studies classified as having low (green), unclear (yellow) or high (red) risk of bias according to different methodological variables