Studies Cement Zika’s|Link to Microcephaly

(CN) — A trio of studies released Wednesday offered further validation of the connection between the Zika virus and a birth defect that causes small heads and potential brain damage in newborns.

Researchers performed a series of tests on mice that demonstrate the virus' ability to cross the placenta during pregnancy and slow brain growth. Additional experiments on animals with larger brains are also needed, according to experts.

The findings add to growing scientific evidence of a direct connection between the virus and birth defects and autoimmune disorders that have occurred in nations across Latin America and the Caribbean during local Zika outbreaks.

One well-documented side effect of Zika is microcephaly, which results in a baby being born with a smaller head and potential brain damage.

There have been more than 1,000 confirmed cases of microcephaly in Brazil since Zika began spreading there this past year.

The data also highlights that Zika infections occurring earlier in pregnancy cause more damage than infections at later stages.

In one of the studies, published in the journal Cell-Stem Cell, Chinese scientists injected a strain of Zika that is closely related to the one circulating in South America into the brains of mice fetuses 13 days after fertilization. The gestation of mice is between 19 and 21 days.

The brain development of mice begins later in gestation than it does in humans, and continues after birth.

The scientists found that the virus replicated rapidly in the developing brain's ventricles, which eventually led to symptoms similar to microcephaly including larger fluid reservoirs and thinner cortical structures.

Findings were limited because the lactating mothers ate their babies two days after birth.

"A mouse model is evolutionarily far removed from a human, so you have to be cautious when you extrapolate," said Anthony Fauci, director of the National Institute on Allergies and Infectious Diseases.

Fauci also said that analyzing the virus' behavior in thousands of virtually identical animals does provide an opportunity for researchers to review Zika's effects — to an extent.

In a study published in the journal Cell, researchers from the Washington University School of Medicine in St. Louis have developed two mouse models of Zika infection during pregnancy that can be used to quickly test experimental Zika drugs in order to prevent or minimize congenital abnormalities.

Their findings could also help scientists understand the virus' effects on pregnant women.

The team's first model Zika infection involved female mice that had been genetically engineered so they could not mount a specific immune response, leaving them susceptible to being infected by Zika.

The virus killed most of the fetuses of these pregnant mice within a week. The fetuses that survived had significant abnormalities, including severely limited growth.

Researchers noted levels of viral genetic material in the mouse placentas that were 1,000 times greater than in the blood of pregnant mice, suggesting that Zika prefers to replicate within the placenta.

The second model featured genetically normal pregnant mice that were given an antibody that suppressed an immune response to the virus. The researchers then infected the mice with Zika one or two days later.

This model showed impaired growth of the mice fetuses but did not lead to death.

Researchers noted that viral genetic material remained in fetal heads and bodies through at least day 16 of embryonic development, which is a critical period for mouse brain development.

The mouse models can be used to quickly determine the effectiveness of candidate drugs and other interventions, the researchers said.

Michael S Diamond, the study's leader author, referenced a recent study by National Institute of Health-funded researchers from the University of Pittsburgh, which found that the immune system protein interferon-lambda inhibits Zika from infecting a key type of human placental cell.

Diamond and his team are planning studies to test whether interferon-lambda can prevent the transmission of the virus from pregnant mice to their fetuses.

The third study, published in the journal Nature, was conducted by researchers at the University of California San Diego School of Medicine and scientists from Senegal and Brazil, and provided direct experimental proof of causal effect of Zika and severe birth defects.

Researchers conducted studies involving mouse models, human stem cells and cerebral organoids — miniature brains grown in vitro — using the strain of Zika spreading through Brazil.

Alysson R. Muotri, one of the senior authors and associate professor in the UC San Diego School of Medicine, said the model his team developed to determine Zika cause-and-effect presents a new tool to asses the effectiveness of various therapies for counteracting the virus during human neurodevelopment.

"Our platform can now be used to understand what is unique about the Brazilian Zika virus and to test drugs to prevent the neurological problems associated with the infection," Muotri said. "Moreover, we now have a robust animal model that will be useful during validation of potential vaccines against the virus."

Newborn mice infected with the Brazilian Zika virus strain through their mothers displayed smaller heads and stunted body growth. Genetic and tissue analyses revealed other abnormalities including eye problems and continued cell death.

"This is the first animal model to document Zika-induced birth defects. It shows that the virus can cross the placenta membrane and infect the fetus," Muotri said.

Muotri also noted the possibility that human babies could develop additional health problems stemming from Zika infections.

"The data in mice also suggest that microcephaly is only the tip of the iceberg. The animals have extensive intrauterine growth arrest, which essentially means poor fetal development in the womb," Muotri said.

The Brazilian Zika virus could not cross the placenta of one strain of mice, which researchers suggest indicates that some individuals are more susceptible to infection than others, mice and humans alike.

The team also generated cortical progenitor cells that typically differentiate into neurons that form the brain's cerebral cortex or folded outer layer. Infecting these progenitor cells with the Brazilian viral strain resulted in increased progenitor cell death, while the effects of the African virus strain was not as significant.

This indicates that mutations of the Brazilian strains made the virus more aggressive in human cells, potentially leading to different health outcomes for infected individuals.

"Media covering the Zika story have focused upon affected babies with small heads because such images are profoundly dramatic, but the true health impact is likely to be more widespread and devastating," Muotri said.

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