Rapid growth of the human population accompanied with urbanization and climate change is creating an environment conducive to the emergence of previously uncommon arboviruses, such as Zika virus (ZIKV). ZIKV poses a substantial public health concern due to the congenital abnormalities associated with ZIKV infection during pregnancy.
Host of Zika virus involves Aedes mosquitoes and primates. The viral determinants required to replicate in such an obligate host are subject to rigorous purification selection during natural virus evolution, so it is difficult to determine which determinants are the best virus fitness in each host.
Morgan Freney is a PhD student in Professor Paul Young’s Lab of the University of Queensland Australia. By 2020, she was a research assistant in Dr. Alexander Khromykh’s Lab. When Morgan was studying at Dr. Alexander Khromykh’s Lab, her research was focused on developing vaccines and therapeutics against mosquito transmitted viruses. She took part in the project of using a deep mutational scanning (DMS) strategy to find out the determinants of Zika virus host tropism. The paper was published in Nature Microbiology on March 18, 2019.
In this study, they have used DMS methodology and selection in mosquito and mammalian cells to identify two substitutions in the ZIKV E protein, K316Q and S461G, that together strongly favoured virus replication in mosquito cells. A mutant virus, 316Q/461G, found to be highly attenuated in human brain organoids, and illustrated utility as a vaccine in mice. Thus, this approach can simulate evolutionary selection and identify key amino acids that regulate virus replication in a specific host environment within a few days.
Zika virus utilise host mRNA degradation machinery to produce subgenomic flaviviral RNA (sfRNA). In mammalian hosts, this noncoding RNA facilitates flavivirus replication and pathogenesis by inhibiting IFN-signalling, whereas the function of sfRNA in mosquitoes remains obscure.
In Morgan’s recent publication, they demonstrate that Zika virus noncoding RNAS suppresses apoptosis and is required for virus transmission by mosquitoes.
In this study, they found that sfRNA-deficient viruses have reduced ability to disseminate and reach saliva, thus implicating the role for sfRNA in productive infection and transmission. They also showed that production of sfRNA alters the expression of mosquito genes related to cell death pathways, and prevents apoptosis in mosquito tissues. Inhibition of apoptosis restored replication and transmission of sfRNA-deficient mutants. They proposed anti-apoptotic activity of sfRNA as the mechanism defining its role in ZIKV transmission.
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