A study published today in Science shows that the Zika virus hijacks a human being protein called Musashi-1 (MSI1) to allow it to duplicate in, and kill, neural stem cells. Almost all MSI1 protein in the developing embryo is produced in the nerve organs stem cells that will eventually develop into the baby’s human brain, which could explain why these cells are so vulnerable to Zika.

Since 2016 thousands of kids across South America have been born with microcephaly, which causes unusually small heads, after their mothers became infected with all the Zika virus during pregnancy. The overlap between Zika situations in pregnant women and an increase in babies born along with microcephaly strongly suggested that the virus targets stem cells within the developing human brain, but why and how has remained the mystery. Today’s study is the first to associate MSI1 with microcephaly and the Zika virus.

Doctor Fanni Gergely from the University of Cambridge said: “The development of a healthy human brain is an incredibly complex process that will relies on stem cells and the coordinated actions of many genetics. We’ve shown for the first time this interaction between Zika plus MSI1 — with MSI1 getting exploited by the pathogen for its own destructive life cycle, turning MSI1 to the enemy within. We hope that in the future this discovery can result in ways of generating potential Zika virus vaccines. ”

Dr Mike Turner, Head of Infection plus Immunobiology at Wellcome said: “This is the first research to show a clear link between a specific protein, the Zika virus and microcephaly. This new finding really helps you to explain why neural stem cells are so vulnerable to Zika infection and I hope this can be a first step in determining the way we could stop this interaction and disease. It will also end up being interesting to investigate whether this protein is involved in additional viruses, such as Rubella, that can also access and hinder the developing human brain. ”

Researchers from your University of Cambridge studied a variety of cell lines, which includes human neural stem cells, to investigate how Zika pathogen infection can lead to microcephaly. They suspected that MSI1 — an RNA binding protein — might be important with this process because it is involved in regulating the pool of nerve organs stem cells that are required for normal brain development.

The researchers show that when the Zika pathogen enters these stem cells, it hijacks MSI1 because of its own replication and damages the cells in at least 2 different ways. Firstly, MSI1 binds to the Zika virus genome letting it replicate and making the cells more vulnerable to virus-induced cellular death. When the researchers infected cells that had been rendered not able to produce MSI1, virus replication was significantly reduced, since was cell death, indicating that the presence of MSI1 is required pertaining to efficient Zika replication.

Secondly, they demonstrated that MSI1 also disrupts the normal development programme associated with neural stem cells. In cells infected with Zika virus MSI1 binds to the virus genome in favour of the normal targets in the cell. The virus essentially acts just like a ‘sponge’, preventing MSI1 from working correctly and changing the expression of many genes involved in neuronal development.

In both of these scenarios, neural stem cells, that are crucial for normal neural development, are lost, resulting in microcephaly.

To confirm that MSI1 is important to develop a normal size brain, the scientists demonstrated that MSI1 is mutated in individuals with a rare type of inherited microcephaly (autosomal recessive primary microcephaly) unrelated to Zika illness.

These results collectively suggest that neural originate cells need MSI1 to generate enough neurons for regular brain size, but the presence of MSI1 also boosts the vulnerability of these cells to Zika infection, leading to the particular death of the population which ultimately results in microcephaly.

This study was funded by Wellcome plus Cancer Research UK.

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