An Engineering Approach to Solving Zika Virus
Assistant Professor Priya Shah studies viruses transmitted by arthropods to understand how to mitigate risk to humans
Priya Shah, who holds appointments in the Departments of Microbiology and Molecular Genetics, and the Department of Chemical Engineering, is deciphering the behavior of the Zika virus on animal cells to delve into the possibilities for mitigating the sickness in humans.
"My lab is really interested in how viruses hijack cells and turn them into little, tiny viral factories," said Shah.
The Zika virus is a type of flavivirus – a virus typically transmitted by arthropods, such as ticks or mosquitos, which is easily spread in more tropical areas. The nature of the virus is to replicate, essentially divide and copy itself, in the most efficient way possible by infecting a host. This can result in the death of host cells followed by an immune response such as a fever or body aches.
Effects of Zika during pregnancy
In most healthy adults, the virus is not lethal. The bigger issue is derived from the virus's ability to infect a developing fetus. During pregnancy, a fetus is protected by the placenta, but Zika virus is unique in that it can breach the protective placental barrier said Shah.
"It can move from the [infected] pregnant person through the placenta all the way to the developing fetus," she explained.
Proteins that nurture a developing fetus in host cells are disrupted by Zika virus. The neural stem cells in a growing brain aren't able to properly divide and differentiate to form neurons. The result of this infection in newborns is a brain disorder called microcephaly. This is when newborns experience severe intellectual disability due to inhibited brain development. Brain volume is gravely reduced around the top of the skull.
To explore the interactions between the virus and the host proteins, Shah employs an approach called proteomics.
"We use this approach to essentially identify who's next to who but on a very large scale," she said, "You can generate thousands of data points in a single experiment."
The challenge with the approach is identifying what is actually meaningful. Shah has a checklist of criteria to filter her data sets. In particular, she highlights protein interactions that are reproducible, abundant and highly specific.
"The key is to compare virus interactions across multiple different viral proteins all at once," Shah said.
Through these approaches, Shah has managed to isolate a human protein called ANKLE2 that interacts with Zika virus's Nonstructural Protein 4A (NS4A). ANKLE2 is expressed in many different human cells. A unique role of the protein is in promoting the growth of brain cells, but it's also important to the virus's ability to replicate.
Using other animal models to understand Zika
Nikki Link, an assistant professor at the University of Utah studying the virus in fruit flies, discovered that the same viral protein NS4A disrupts ANKLE2 in fruit flies.
"This limits the development of important stem cells which causes brain volume to be much smaller," says Shah.
These results bring Shah's team one step closer to understanding the specific areas that the Zika virus invades to cause microcephaly.
To study brain development in mammals affected by Zika virus, Shah utilizes the abundance of animal models offered at UC Davis.
To further her research, the lab has sought to study Zika in more vertebrate models including zebrafish and mice. Compared to flies, these animals have brain development that more closely reflects human brain development.
The pursuit of such a specific finding of the virus' nature comes with its challenges. Shah highlights the difficulty of Zika's nature with aspects such as time and unpredictable behavior as factors to work around.
Real-world impacts of research
Despite those challenges, Shah has driven the real-world impact of her research. Mosquito-borne flaviviruses are prevalent in India, her country of ancestry, and "studying viruses that are common to that region of the world is inspiring to me."
Along with this connection, she is consistently fascinated by how viruses have evolved over the millions of years they have existed.
The discovery of the interactions of the Zika virus fuels the interest of other flavivirus models. Some of these were noted by Shah, including yellow fever virus.
"We are working on yellow fever virus," Shah shared. "Our hope is to help explain how yellow fever virus turns a cell into a little viral factory, but also how this virus causes disease at the same time."
Priya's work with Zika virus deviates from more conventional engineering projects in its heavy applications of microbiology.
As an engineer though, Shah is able to bring a "quantitative perspective to viruses because [you] just think about things in a slightly different way."