In 2015, a little-known mosquito-borne virus called Zika began making international headlines when it spread throughout Latin America. Thousands were infected, including pregnant women who subsequently gave birth to babies with microcephaly — a birth defect characterized by an undersized head and brain. Reports of Zika cases began appearing elsewhere, including the United States and San Diego County.

While that outbreak ended in 2017, research on the virus continues. In a study published May 6, 2019 in Scientific Reports, Adriano de Bernardi Schneider, PhD, postdoctoral researcher at UC San Diego School of Medicine and Michael T. Wolfinger, PhD, a researcher at the Theoretical Chemistry Department of the University of Vienna, helped unravel Zika virus’ affinity for the brain.

Schneider helps us break it down:

What was the motivation for this study?

While the Zika virus has been associated with congenital neurodegenerative disease — especially fetal microcephaly — the biological reasoning and mechanisms as to why the Zika virus has an affinity for the nervous system are still unknown.

Recent studies have suggested that a human protein called Musashi is involved in Zika’s connection to the human brain. The Musashi protein is typically expressed in neural stem cells and is required for brain development. Now we also know it’s involved in Zika virus replication.

With that in mind, we focused on understanding the theoretical model underlying the Zika virus binding with Musashi proteins, and expand the knowledge to other related viruses from the same group, known as Flavivirus. Flaviviruses include more than one hundred different virus species, many of them global threats transmitted by mosquitoes and ticks. Flavivirus outbreaks are frequently found in equatorial regions of the world and cause hundreds of thousands of infections in humans every year. The last Zika virus outbreak occurred in the Americas from 2015 to 2017.

What did you find?

Our findings showed that among the flaviviruses, Zika virus has the highest affinity for binding by the Musashi proteins. Moreover, we showed that other flaviviruses have a similar Musashi-binding potential, indicating that Zika may not be the only flavivirus that can cause this type of damage to the nervous system. We also established a theoretical model for the affinity of Musashi proteins to binding flaviviruses, and therefore enhancing their replication. This approach could be expanded to other viral families.

Left: Study co-authors Michael T. Wolfinger and Adriano de Bernardi Schneider present their work at a conference. Right: Zika virus structure, courtesy of the NIH.

What’s surprised you?

The fact that the affinity for Musashi proteins was highest for the Brazilian Zika virus isolates — though maybe we shouldn’t have been surprised by that, given that most Zika virus-related microcephaly cases in the 2015-2017 outbreak were reported in Brazil. We were also surprised that other flaviviruses seem to have a similar affinity for the brain, which might have been overlooked so far due to the lack of recent outbreaks.

What was (or continues to be) a challenge?

The current challenge is not only to understand what happened in the past, but what is coming next. Like Zika virus, we often have little to no information about a flavivirus when it suddenly emerges, creating a burden for the populations affected.

What’s next?

Now we plan to look into other viruses that affect fetal and newborn brains. Also, we need further wet laboratory studies that can test our hypothesis on relatively obscure viruses that we flagged as potentially affecting the brain, such as Nounané virus and Karshi virus.

- Heather Buschman, PhD