Distinct evolutionary pressures discovered in vertebrate animals compared to mosquito vectors can protect humans and animals from flavivirus infections

Published on
April 23, 2021

The genus Flavivirus contains many pathogenic vertebrate-infecting flaviviruses (VIFs) including Zika virus, West Nile virus, dengue virus, yellow fever virus and Japanese encephalitis virus. These viruses are transmitted between humans and other vertebrate hosts by mosquito vectors. In addition to these VIFs, multiple closely related insect-specific flaviviruses (ISF) have been identified in mosquitoes. Some of these ISFs are even able to adhere to and enter vertebrate cells. However, despite their close phylogenetic relationship with VIFs, multiple studies show that these ISFs cannot replicate inside vertebrate cells.

Vertebrate cells contain antiviral pathways that can detect non-self RNA by the way the four building blocks of the genetic code are used and ordered. Most vertebrate infecting viruses have adapted to resemble host RNA composition and, in this way, evade this antiviral pathway. Interestingly, the definition of self-RNA is very different in insect cells compared to vertebrate cells and as a result insect-specific viruses have adapted to mimic insect RNA composition, resulting in notable differences between the genetic codes of VIFs and ISFs.  In a recent publication, Wageningen virologists and collaborators showed that the vertebrate antiviral pathway that recognizes non-self RNA sequences is key to protect human cells from infection by insect-specific flaviviruses and that without this antiviral pathway, human cells are susceptible to insect-specific flavivirus infections.

In a second study, the mosquito-borne VIF Zika virus was used to investigate how a virus is able to alternate between vertebrate hosts and mosquito vectors when the evolutionary pressures on the viral genome in both organisms is clearly so distinct. Mutant viruses were created that more closely resembled the composition of mosquito RNA and found to be more infectious in mosquitoes.  At the same time, these ‘insect-optimized’  mutant Zika viruses showed reduced fitness compared to wildtype virus in vertebrates. Moreover, a vaccine challenge experiment showed these mutant viruses completely protected mice from tissue damage by subsequent pathogenic Zika virus infections.

Together, Wageningen virologists showed that a newly discovered antiviral pathway is key to protect vertebrate cells from insect-specific flavivirus infections and that by optimizing the genetic code of pathogenic flaviviruses for replication in the mosquito vector these viruses are exposed to vertebrate  antiviral responses resulting in virus attenuation. This strategy can theoretically be applied to many viral families with potential as a vaccine platform and possibilities to optimize virus replication and protein production systems in insect cells.