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The Zika virus, transmitted by mosquitoes, has gained notoriety for its link to microcephaly, a significant birth defect characterized by underdeveloped brain structures leading to a smaller head size. A recent study published in mBio on January 13 highlights how Zika exploits a host protein named ANKLE2, which is crucial for fetal brain development, to further its own replication. This capability is particularly troubling as Zika can traverse the placental barrier, presenting serious risks during pregnancy.
“Zika finds itself in an unfortunate scenario,” remarked Priya Shah, an associate professor at the University of California, Davis, and the lead researcher of the study.
The research reveals that other related viruses, such as dengue and yellow fever, similarly exploit the ANKLE2 protein for their replication needs. This discovery opens potential avenues for developing new vaccines or therapeutic interventions against these viruses.
Viruses possess a limited genetic code, which necessitates their dependence on commandeering host cellular proteins and mechanisms for reproduction. Shah’s research group has been examining these critical interactions.
Previously, the team found that a specific Zika protein known as NS4A interacts with ANKLE2 within host cells, providing insights into how this virus could lead to microcephaly.
While ANKLE2 is integral to brain development, it is also expressed in various other cell types throughout the body.
Creating Viral Replication Sites
In the latest research, which was spearheaded by doctoral graduate Adam Fishburn, the team cultured Zika virus in human cells. By disabling the ANKLE2 gene in those cells, they observed a significant reduction in the virus’s replication ability.
In human cells infected with Zika, ANKLE2 aggregates near the endoplasmic reticulum, the cell’s protein production hub.
Shah explained that the viral NS4A protein interacts with ANKLE2, forming specialized areas adjacent to the endoplasmic reticulum that act as factories for viral production. This localization of replication machinery enhances the efficiency of the virus’s reproduction while also evading immune detection.
“While ANKLE2 is very important for creating these replication sites, it is not absolutely necessary,” Shah noted.
Fishburn added that although human cells possess robust defenses against viruses, they must first locate the intruders. “Zika and other similar viruses have evolved tactics to conceal themselves within these replication sites. We believe that the hijacking of ANKLE2 facilitates this evasion. Without ANKLE2, these replication sites are less effective, allowing the immune system to more effectively curtail viral replication,” he explained.
Collaborating with researcher Claudia Rückert from the University of Nevada, Reno, the team found that Zika virus also targets ANKLE2 during infections in mosquito cells, underscoring the significance of this interaction in both human and insect hosts. Moreover, they demonstrated that NS4A from other mosquito-borne viruses, including dengue and yellow fever, similarly interacts with ANKLE2, suggesting that this relationship is critical for replication among a range of mosquito-borne viruses. This insight may pave the way for novel therapeutic strategies targeting these diseases.
The question arises: Why do more prevalent viruses like dengue not result in microcephaly like Zika does? The answer likely lies in the unique ability of Zika to penetrate the placenta, reaching the fetal environment where ANKLE2 plays a vital role in brain development. In contrast, many other viruses are typically barred from entering the fetus due to the protective placental barrier.
This research was funded by the National Institutes of Health and the W. M. Keck Foundation. The team included additional contributors from UC Davis and other institutions, including the University of Nevada, Reno, and the Icahn School of Medicine at Mount Sinai, New York.
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