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The ability to take control of cells that give rise to the skull may be key to Zika virus’ crippling effects on infants’ brain.

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Researchers found that Zika hijacks cells related to skull formation to produce excess molecules that damage neural progenitor cells, which give rise to different types of brain cells. The infection of these cells may explain why babies born to mothers affected by the virus have smaller-than-average heads—a condition known as microcephaly.

“Some of the babies born to mothers affected by Zika not only have small brains, they also have facial abnormalities,” said Catherine Blish, one of the lead authors of the study. This detail spurred her and co-author Joanna Wysocka’s teams to focus on a group of cells, dubbed cranial neural crest cells, which develop into different head structures, including bones of the face.

The infection of cells related to skull formation may explain why babies born to mothers affected by Zika have smaller-than-average heads.

Previous research had focused on the effects of Zika infection on cells that give rise to neurons. According to Ralph Marcucio, a developmental biologist at University of California San Francisco who was not involved in the research, this study helps shift the attention to other cell types. “[Cranial neural crest cells] would not be the first suspects of causing microcephaly,” he said.

When the researchers added Zika virus to cranial neural crest cells in a laboratory dish, the virus not only infected those cells, but it was also able to hijack them to support its own growth. One day after infection, the number of viruses in the dish increased up to tenfold.

Surprisingly, Zika did not kill the cells, Blish said. Infected cranial neural crest cells did, however, affect healthy neural progenitor cells—cells that give rise to different types of brain cells such as neurons. When the two cell populations were grown together, neural progenitor cells changed their shape or died, despite the fact that they were not infected with Zika—the two groups of cells were separated by a thin membrane that prevented viruses from passing through.

To explain these results, the researchers had to look elsewhere. They knew that, during the first stages of pregnancy, cranial neural crest cells occupy a region next to the developing brain and communicate with it through chemical messengers known as cytokines. “Cytokines tell the developing brain when to develop and how,” Blish said.

Zika-infected cranial neural crest cells produced 60 times more cytokines than non-infected cells. Since cytokines are small molecules that could easily cross the membrane used in the experiments, the researchers hypothesized that the excess of cytokines produced by infected cranial neural crest cells may be the culprit of the damage to neural progenitor cells. Indeed, adding large amounts of cytokines to neural progenitor cells grown alone made them alter their shape or die earlier than expected.

Infected cranial neural crest cells may impair brain development by acting as a reservoir of new viruses and producing cytokines at unhealthy levels. According to Blish, the communication breakdown caused by the excess cytokines might cause microcephaly in some pregnant women. However, more experiments in living animals are needed to prove this connection.

Andrea Da Poian, who studies virus-host interaction at the Federal University of Rio de Janeiro and was not involved in the research, pointed out that, although interesting, this is still only a hypothesis. According to Da Poian, because of the complexity of brain development, there is a long way to go before it will be possible to prove the effects of Zika infection on microcephaly.

Marcucio echoed the need for more experiments in animals. “What is true in a laboratory dish might not be true in a living animal,” he said.

Marcucio is intrigued by the idea that Zika could co-opt normal signals to disrupt the flow of information to the brain. “This work highlights the importance of a two-way communication between the brain and other cell types, especially in disease situations,” he said.