Zika has a trick
Once inside the body, the virus forms dendritic cells, which we rely on to initiate an effective immune response
"Dendritic cells are the primary cells of the innate immune system," said Dr.
Sujan Shresta, a professor at LJI and a member of the LJI Center for Infectious Diseases and Vaccines
"How is this virus so smart enough to establish infection in cells that would normally fight it?"
Now, Shresta and his colleagues at LJI and the University of California, San Diego have found that the Zika virus actually forces dendritic cells to stop functioning
as immune cells.
Using a new model of Zika virus infection, the LJI team showed that Zika virus causes dendritic cells to produce lipid molecules in large quantities, which the virus uses to replicate itself
The study is a big step forward in the work of Shresta's lab, which directs the design of new antiviral therapies to combat many members of the flavivirus family, including Zika virus, dengue fever and The Japanese encephalitis virus (JEV
"Understanding how viruses interact with human cells is critical to understanding how infections can be treated or prevented in the future," said
Aaron Carlin, a professor at the University of California, San Diego.
Emilie Branche, a former postdoctoral fellow at LJI, led a work to develop a model to better understand how Zika and dengue viruses target dendritic cells
Her research interests are human immune cell monocytes, which she promotes the differentiation of monocytes into dendritic cells
Branches analyzed how gene expression in these dendritic cells changed during Zika or dengue infection
She then compared
the changes in gene expression to those in the cells she suffered from "simulated infection.
" This contrast reveals exactly how Zika virus dominates
The researchers found that zika virus manipulates genes
in dendritic cells that control lipid metabolism.
The virus invokes a cellular protein called SREBP, which forces the production of lipids or fat molecules to accelerate
These lipids became the cornerstone for assembling new copies of Zika virus — copies intended to spread throughout the body, further exacerbating the infection
"We show that Zika virus (as opposed to dengue) regulates cellular metabolism to increase its replication
," Branche said.
The team then investigated whether zika virus converts other cells into lipid factories
While Zika virus also targets neuronal precursor cells, the researchers showed that Zika virus does not manipulate lipid metabolism genes
in these cells.
Shresta was surprised to find that these changes only occurred in dendritic cells, and she was surprised to find that Zika virus (not dengue fever) altered lipid production
"These viruses are crazy," Shresta said
"How these viruses manipulate the response of host cells is very virus-specific and cell-type-specific
The next step is to develop antiviral drugs that prevent Zika virus from using lipids to metabolize genes
The new study suggests that therapeutically silent SREBP may offer hope
How to deal with dengue fever, the cousin of Zika virus? Because these viruses are so closely related and overlap in many places, Shresta believes that SREBP inhibitors are just one component in a "cocktail" of inhibitors that treat a variety of different flavivirus infections
"The more we learn about these viruses, the closer we get to 'yellowing virus' inhibitors
," she said.
SREBP2-dependent lipid gene transcription enhances the infection of human dendritic cells by Zika virus