Effect of antibody-dependent enhancement on the development of the offspring of mice infected by Zika virus: Analysis of the brain transcriptome.

Zika virus (ZIKV) is an arbovirus associated with neurological complications such as neonatal microcephaly and fetal anomalies, collectively referred to as congenital Zika syndrome. In the context of co-circulation with other arboviruses, it remains unclear whether pre-infection with a virus could be a risk factor for increased severity of ZIKV-induced disease. Here, we aimed to investigate whether there is differential gene expression in offspring of ZIKV-infected mothers pretreated with panflavivirus (4G2) at subneutralizing concentrations. Twelve weeks after birth, the offspring of these mothers were euthanized and their cerebral cortex was sampled for transcriptome analysis. Subsequently, the major differentially expressed genes (DEGs) were validated by RT-qPCR. Our results show that ZIKV infection induced fewer DEGs compared to the uninfected group, with the main findings being a suppression of genes related to cell cycle and morphogenesis. However, genes related to activation of the immune response and production of inflammatory mediators were preferentially expressed in the offspring of 4G2-treated mice compared to infected mice. Suppression of cellular and morphological processes was also observed, supporting ZIKV pathogenesis, particularly in the developing nervous system. The genetic and metabolic changes observed by transcriptomic analysis are therefore consistent with the more severe phenotypic observations in adult mice in previous studies. Our results contribute to the understanding of the severity of congenital ZIKV infection in the context of cross-reactivity of antibodies against other flaviviruses.