Three separate studies released Wednesday present the first batch of mouse model data on what happens when the Zika virus infects a pregnant mammal — and the data is as gruesome as one would expect.
The three studies, led by research groups in Brazil, the US and China, support the grim human epidemiological data linking the virus to miscarriages and birth defects, most notably microcephaly, a condition in which babies are born with small and misshapen brains.
Collectively, the new studies highlight that when Zika infects a pregnant mouse, the virus lodges in the developing fetuses and invades the placenta and fetal brain in large numbers. In one of the studies, viral counts in the placenta were 1,000 times higher than in the mother’s blood. Once in the fetal brain, the virus specifically attacked developing and mature neurons, leading to cell death, confused immune responses and severe brain malformations. In another study, researchers noted that the number of viruses in a fetus’s brain increased by about 300 percent within three days of invasion. Many of the pups in the studies died in the womb, while others were quickly eaten by their mothers after birth — a common reaction of mice to the birth of sick pups.
While Zika’s ferocity in the unborn is staggering, the mouse model data doesn’t yet tell us any new facts about the devastating virus, which is currently rampaging through South and Central America. Rather than new insights, the excitement of the studies comes from the mouse models themselves. Now that researchers have worked out procedures to infect the rodents in a way that causes infections and causes birth defects, researchers can replicate the methods to ask new questions about the biology of the virus and test potential new therapies.
It wasn’t easy to get to these models; mice usually don’t suffer much from viruses like Zika, a member of a viral family called Flaviviruses that includes dengue and yellow fever. The three research groups each devised their own tricks to detect infections in mice.
The research group from Beijing, China eventually injected an Asian strain of Zika directly into the brains of fetal mice in the womb. The researchers performed the injection about midway through pregnancy — equivalent to the second trimester in human terms — because they found that previous infections would simply kill the pups. After the infection, the researchers monitored the pups and noted how the number of viruses increased by a factor of 300 in the first three days, destroying the developing neurons and shrinking the brain. Their results appear in the journal Cell Stem cell.
In another study published in Cellresearchers at Washington University in St. Louis diagnosed Zika infections in pregnant mice by shutting down the rodents’ immune systems in two different ways. First, the researchers genetically engineered mice with defective type I interferon signaling, the body’s alarm system for viral infections. Infecting these pregnant mice with a French Polynesian strain of Zika ultimately led to the fetal death in the womb. In the second model, the researchers stopped type I interferon signaling using antibodies, which weakened but did not destroy immune responses. Fetuses in this model survived but still became infected with Zika in utero. The researchers watched as viral loads exploded in the placenta, passed into fetal brains and wreaked havoc on the unborn pups.
In the latest study, published in Nature, researchers at the University of São Paulo injected a relatively high dose of a Brazilian strain of the Zika virus into pregnant mice, causing infections. The researchers also compared the infections caused by the Brazilian strain with those of the African strain, which was isolated in Uganda in 1947. . While the finding isn’t surprising (and may have been exaggerated by the African strain’s long passage into labs, where it could have lost some of its potency), the finding raises more questions about how the virus evolved to infect fetal brain cells. brutal attack.
With these new models, researchers will begin to get answers to those questions, the authors of the Nature study said.
Cell Stem cell2016. DOI:10.1016/j.stem.2016.04.017 (About DOIs).
Cell2016. DOI: 10.1016/j.cell.2016.05.008