In 2016 the Zika virus emerged as an urgent global health priority, prompting researchers throughout the world to focus on better understanding this rapidly spreading condition and its devastating side effects, including brain malformations and other birth defects in unborn babies.
Research to date demonstrates that the Zika virus attacks key cells responsible for generating neurons, as the brain grows during embryonic development. Previous studies had suggested that Zika enters these cells, called neural progenitor cells or NPCs, by attaching to a protein named AXL on the cell’s surface. This early research showed that blocking the expression of the AXL receptor protein defends against the virus in several human cancer cell lines. Since the protein is highly expressed on the surface of NPCs, many researchers have speculated that AXL is the entry point for Zika in the developing brain.
Now scientists at the Harvard Stem Cell Institute (HSCI) are utilizing state-of-the-art technologies including induced pluripotent stem cells (iPSCs) and genome editing to more closely examine NPCs, have found AXL is not the only entrance point for Zika during infection.
“We demonstrated that getting rid of the AXL receptors did nothing—it didn’t slow the virus down at all. This data completely reset the field and has led researchers back to the drawing board to search for other critical Zika receptors in NPCs,” says Kevin Eggan, PhD, professor of stem cell and regenerative biology at HMS, principal faculty member at HSCI, and co-corresponding author of a Cell Stem Cell paper describing this research.
Armed with this new knowledge, Eggan and his colleagues have formed a unique collaboration with Novartis to formally test NPCs via two types of genetic screens to more acutely understand the role these cells play in Zika infection.
“One of the nice things about working with Novartis is they can run these screens in a short amount of time. We can remove each protein from the cell individually and determine which deletion prevents Zika infection. We have not been able to test these proteins so quickly and efficiently before,” says Michael Wells, PhD, a postdoctoral fellow in the Eggan Laboratory.
Eggan adds, “We need to get a sense of whether or not there can be any benefit from this strategy—if there are 50 ways Zika can enter through these cells, it’s going to be hard. We need to find what the choke point is; a more strategic location we can focus on.”
Eggan and his colleagues will use the transcriptional data they already have on NPCs and create a list of protein candidates to cross-validate against data from the genetic screens.
“We are looking for yes or no answers—can we target a single protein in the NPCs and have a large effect? If the answer is no, we will turn to other locations to stop the infection. For instance, maybe we can prevent the virus from getting into the fetus by stopping transmission through the placenta. We remain hopeful that pursuing these avenues of research will lead to improved patient outcomes in the future,” Eggan says.
Lauren Carr is a freelance science writer based in Massachusetts.