The Zika virus, transmitted by mosquitoes, is recognized for causing microcephaly, a birth defect characterized by underdeveloped brains resulting in smaller head sizes. A recent study highlights that the Zika virus takes control of a host protein known as ANKLE2, which is crucial for brain development, to aid in its reproduction. This is particularly problematic since Zika virus is capable of crossing the placenta, leading to potentially severe consequences during pregnancy.
The Zika virus, which is spread by mosquitoes, has been linked to microcephaly, a condition where abnormal brain growth results in a smaller-than-normal head. A new research published on January 13 in mBio reveals that the Zika virus exploits a host protein named ANKLE2, essential for brain development, for its own replication. Since Zika can cross the placenta, it poses significant risks during pregnancy.
“Zika is in the wrong place at the wrong time,” stated Priya Shah, an associate professor in Microbiology and Molecular Genetics as well as Chemical Engineering at the University of California, Davis, and the lead author of the study.
The findings also demonstrate that related viruses, such as dengue and yellow fever, utilize ANKLE2 for similar purposes. This breakthrough could pave the way for developing new vaccines or treatments against these viruses.
Viruses possess a limited genetic blueprint, so they must commandeer host cell components to reproduce. Shah’s lab focuses on understanding these virus-host interactions.
In previous work, Shah’s team discovered that a Zika protein named NS4A interacts with ANKLE2 within host cells, which could potentially lead to microcephaly when tested in Drosophila fruit flies.
While ANKLE2 is crucial for fetal brain development, it is present in various cells throughout the body.
Creating virus factories
In this new study, led by Ph.D. graduate Adam Fishburn, Shah’s group cultivated Zika virus in human cells. Deleting the ANKLE2 gene in these cells significantly impaired Zika virus growth.
In cells infected with Zika, ANKLE2 clusters around the endoplasmic reticulum, which serves as a network for protein synthesis within the cell.
According to Shah, the viral protein NS4A collaborates with ANKLE2 to create pockets off the endoplasmic reticulum, which function as factories for virus production. Concentrating all the components needed for virus creation in a single location enhances replication efficiency and conceals the virus from the immune system.
“Our current understanding is that while ANKLE2 is crucial, it is not absolutely necessary for forming these replication pockets,” Shah noted.
Fishburn commented that our cells are generally well-equipped to fight off viruses, but only if they can detect them.
“Zika and similar viruses have evolved to hide within these replication pockets to elude detection. We suspect that ANKLE2 is co-opted to facilitate this, and that without it, the replication pockets don’t form as effectively, allowing the immune system to limit virus replication,” Fishburn explained.
Collaborating with Claudia Rückert from the University of Nevada, Reno, they discovered that Zika virus also utilizes ANKLE2 when infecting mosquito cells, indicating the significance of this interaction in both human and insect hosts. Furthermore, they established that NS4A from other mosquito-born viruses, such as dengue and yellow fever, also interacts with ANKLE2 similarly. This suggests that the NS4A/ANKLE2 connection is vital for replication across a wide range of mosquito-borne viruses, potentially leading to novel drug and vaccine solutions for these illnesses.
Given that common viruses like dengue target ANKLE2, why don’t they cause microcephaly like Zika does? The answer likely lies in their location. The Zika virus is unique in its ability to cross the placenta and enter the fetus, where ANKLE2 plays a significant role in brain development. Most other viruses are usually kept from entering the fetus due to the protective placental barrier.
This research received support from grants provided by the National Institutes of Health and the W. M. Keck Foundation. Additional contributors to the study include Cole Florio, Thomas Klaessens, Neil Alvin Adia, Nicholas Lopez, Nitin Sai Beesabathuni, Sydney Becker, Liubov Cherkaschenko, Sophia Haggard Arcé, Vivian Hoang, and Traci Shiu from UC Davis; Brian Prince from University of Nevada, Reno; and Blake Richardson and Matthew Evans from Icahn School of Medicine at Mount Sinai, New York.
