Study identifies two Zika proteins responsible for microcephaly

Researchers at the University of Southern California have identified two Zika proteins believed to be responsible for microcephaly, taking the first step towards preventing Zika-infected mothers giving birth to babies suffering from the condition.

Zika contains ten proteins but it is the two identified, NS4A and NS4B, which matter in cases of microcephaly, according to the study. The research is said to be the first to examine three strains of Zika in second trimester human foetal neural stem cells, as well as the first to examine the virus at a molecular level.

“We now know the molecular pathway, so we made the first big step toward target therapy for Zika-induced microcephaly,” Jae Jung, senior corresponding author and distinguished professor and chair of the Department of Molecular Microbiology and Immunology at the Keck School of Medicine of USC said.

“Years from now, one shot or a series of shots could target the proteins NS4A and NS4B or their collaborators.”

A Brazilian health department worker exterminates mosquitos that may carry the virus. Image courtesy of Agência Brasília. Above: The impact of microcephaly on brain development. Image courtesy of brar_j

A Brazilian health department worker exterminates mosquitoes that may carry the virus. Image courtesy of Agência Brasília. Above: The impact of microcephaly on brain development. Image courtesy of brar_j

In April, it was confirmed by the Centres for Disease Control and Prevention that the Zika virus causes microcephaly and other severe foetal brain defects, but the reason it did so was unknown. Jung’s team’s findings explain the molecular mechanisms that lead to these conditions.

“This field moves so fast; however, no one has examined the viral proteins in Zika before,” said Jung, holder of the Fletcher Jones Foundation chair in molecular microbiology and immunology.

“The scientific community knows what the Zika virus does but not who is responsible. It’s the difference between saying this nation’s Olympic team earned a gold medal or saying the swim team won the gold medal. My lab is scrutinizing the jobs Zika proteins have in the creation of disease.”

The specific operation of the Zika proteins was found to be the interruption of the Akt-mTOR pathway, a cellular signalling gatekeeper that guards brain development and autophagy regulation –the process of cell recycling. While autophagy usually breaks down and kills pathogens, viruses like Zika, part of a family called flaviviruses, are able to proliferate via the processes of autophagy.

Neural cells infected with Zika virus. Image courtesy of Sarah C. Ogden, Florida State University, Tallahassee

Neural cells infected with Zika virus. Image courtesy of Sarah C. Ogden, Florida State University, Tallahassee

By hijacking foetal neural stem cells, the NS4A and NS4B proteins were found to, on average, halve the size of brain organoids. Moreover, they stunted the growth of the stem cells by 65%  and reduced the differentiation of neural stem cells into mature brain cells by up to 51%.

Zhen Zhao, corresponding co-author and an assistant professor of research physiology and biophysics, has said that they are already working on models to better demonstrate the functions of the Zika proteins, as well as looking into effective biomarkers to indicate necessary intervention into a Zika-infected woman’s pregnancy.

“It is important to remember that not every pregnant woman infected with Zika virus gives birth to a baby with microcephaly,” Zhao said. “Nevertheless, we are trying to develop a cure for that percentage that does get Zika-related microcephaly.”

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