In 2015, an outbreak of Zika virus (ZIKV) in the Americas began to garner global attention owing to its high pathogenicity, causing a range of congenital abnormalities. This ensued a surge in research to dissect the molecular mechanisms of developmental symptoms, most notably neurological symptoms, and implicated the inhibition of a wide range of host pathways by multiple ZIKV proteins.
To investigate these mechanisms further, Nichole Link, Shinya Yamamoto and colleagues generated a toolkit of transgenic flies expressing all ten ZIKV proteins, including three structural proteins and seven non-structural proteins, either systemically or in specific tissues. The authors then performed a series of phenotypic assays to screen the impact of these viral proteins on the developing nervous system. Expression of all viral proteins, apart from the structural protein Capsid, induced scorable yet diverse and tissue-specific phenotypes. Notably, the authors validated previous findings that expression of the non-structural protein NS4A induced microcephaly and determined that expression of NS4B and the NS2B::NS3 fusion caused a similar phenotype.
As there is increasing evidence of post-developmental effects of ZIKV proteins on neuronal function, the authors then expressed ZIKV proteins in post-differentiated photoreceptor cells in the Drosophila eye. The authors showed that post-differentiated neurons expressing NS4A are functional in young flies but become less functional or degenerate as the flies age.
The authors also demonstrated that Drosophila can be used to study the pathogenic consequences of viral evolution. They determined that expression of ZIKV proteins with mutations associated with either the strain from the 2015 epidemic or a strain isolated prior to the epidemic induced phenotypes with differing severity in the flies.
Overall, these findings encourage further investigation into how co-expression of multiple ZIKV proteins can impact a network of host pathways and how this influences the spectrum of clinical presentation. The research team have developed a screening system in Drosophila that will facilitate this research and enrich our understanding of the mechanisms of ZIKV-induced neural symptoms that arise both during development and later in life.
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