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Microcephaly, a birth defect characterized by abnormal brain development and a smaller-than-expected head, is a well-documented condition caused by the mosquito-borne Zika virus.
A study published in mBio on January 13 demonstrates that the Zika virus exploits a host protein known as ANKLE2, which is crucial for brain development, to facilitate its own reproduction. Zika’s ability to cross the placenta, in contrast to the majority of related viruses, can result in dangerous pregnancy outcomes.
The new research demonstrates that ANKLE2 is utilized for the same purpose by related viruses, such as the dengue virus and yellow fever virus. The discovery has the potential to facilitate the development of new methods for the development of vaccines or therapeutics against these types of viruses.
Viruses have a limited number of instructions in their genetic material, which is why they require taking on the functions and proteins of the host cell in order to reproduce. These interactions between the virus and the host are the subject of the laboratory research.
The research team previously discovered that ANKLE2 interacts with NS4A, a Zika virus protein, in host cells. They demonstrated that this could result in microcephaly by employing Drosophila fruit flies.
ANKLE2 is a protein that is present in cells throughout the body and is known to be involved in brain development in the embryo.
The researchers successfully developed Zika virus in human cells. The Zika virus’s growth capability was reduced by the deletion of the ANKLE2 gene in these cells.
In cells infected with Zika, ANKLE2 accumulates in regions surrounding the endoplasmic reticulum, a network that is responsible for protein production within the cell.
The researchers stated that viral NS4A interacts with ANKLE2 to establish virus factories that are located outside the endoplasmic reticulum. Assembling all the components necessary for virus production in a single location enhances the efficiency of replication and also conceals the virus from the immune system.
The current model suggests that ANKLE2 is significantly crucial, but not essential, in the formation of these replication regions.
They also stated that the cells are capable of combating these viruses, provided that they can locate them.
In order to evade detection, Zika and related viruses have developed strategies to conceal themselves within these replication pockets. The researchers hypothesize that ANKLE2 is taken over to aid in the facilitation of this process. In the absence of ANKLE2, the immune system is able to maintain virus replication in check and the pockets do not form properly.
They discovered that the Zika virus also employs ANKLE2 when it infects mosquito cells, indicating that this interaction is significant in both human and insects hosts.
Lastly, they demonstrated that NS4A from other mosquito-borne viruses, such as dengue virus and yellow fever virus, interacts with ANKLE2 in a similar manner. This all indicates that the NS4A/ANKLE2 connection is crucial for the replication of a wide range of mosquito-borne viruses, potentially facilitating the development of novel drugs and vaccines for these illnesses.
If viruses that are much more prevalent, such as dengue virus, also target ANKLE2, why do they not also induce the microcephaly observed in Zika virus infection? It is likely that the sole factor is the location.
The Zika virus is unique in that it has the ability to cross the placenta and penetrate the fetus, a region where ANKLE2 is known to be critical for brain development. The placental barrier prevents the majority of viruses from entering the fetus.
Sources:
Microcephaly protein ANKLE2 promotes Zika virus replication, mBio (2025). DOI: 10.1128/mbio.02683-24
https://phys.org/news/2025-01-wrong-zika-virus-hijacks-protein.html
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