Zika virus causes birth defects in mice

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Zika virus, marked with red, infects a mouse placenta. The nuclei of the placental cells are marked blue.
Credit: Bin Cao

Unambiguous evidence that the mosquito-borne Zika virus crosses the placenta and causes birth defects has been reported in three new studies in mice published today.

Since news emerged last October linking a Brazilian outbreak of the then-little-known Zika virus to a surge in birth defects, researchers have been scrambling to shore up the link.

Now, they have done just that.

In one study, researchers in Brazil, the US and Senegal infected pregnant mice with the Brazilian strain of Zika. In one mouse strain, but not another, the developing pups also became infected. Zika was detected at particularly high levels in the brains of the pups, suggesting the virus homes in on neural tissue.

Importantly, infected pups also developed the same birth defects that have been seen in human babies. The most prominent is a condition called microcephaly, where babies have a smaller than normal head.

Infected mouse pups had signs of microcephaly, the result of “huge amounts of cell death” in their developing brains, explains Jean Pierre Peron from the University of São Paulo in Brazil and author of the paper published in Nature.

The team further demonstrated the damaging effects of Zika in human brain organoids, “mini-brains” that are grown in a test tube and mimic some of the basic structures of real brains. Zika stunted the growth of the organoids, just as it did the pup brains.

A second study in Cell Stem Cell, which directly injected Zika into the brains of developing mouse foetuses, saw microcephaly develop within days of infection before the pups had reached full term.

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Size of Zika virus-infected vs. uninfected foetal mouse brains.

“It was kind of a surprise,” says Zhiheng Xu, from the Chinese Academy of Sciences, who led the study. “We hadn’t thought we could get microcephaly before birth.”

And in a third study in Cell, Michael Diamond and colleagues at Washington University in St Louis infected pregnant mice with compromised immune systems. They reported cases of spontaneous abortion and growth restriction, both of which have been linked to the Zika outbreak in humans.

The virus severely damaged the placenta, which could explain why pups either abort or fail to grow to a normal size.

Together, the papers provide direct experimental evidence that Zika is the sole cause of the birth defect crisis that continues to spread through the Americas.

Although there was speculation that additional factors such as prior infection by the related Dengue virus might be required for birth defects to develop, these new studies effectively rule out that possibility.

Zika acts alone wreaking havoc on foetuses.

The papers also establish the mouse as an important animal model system for further research.

“There are so many open questions,” says Xu. The fact that Zika isn’t able to infect all mice strains points to genetics playing a key role in determining why some people escape Zika’s wrath and others don’t. Diamond notes that mice are a good system for unravelling the genetic basis of these differences.

Perhaps more crucially, the development of vaccines or anti-viral therapies against Zika will rely on a robust experimental system that reflects what’s happening in humans. Preclinical trials in mice will now be a good place to start.

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