A single mutation may explain why Zika suddenly erupted from obscurity to become the alarming re-emerging infectious disease it is today, researchers report in Nature.

According to researchers from Texas and China, the mutation boosts Zika’s ability to hop into feasting mosquitoes that can then shuttle the virus to more victims. Based on archived viral strains, the mutation popped up sometime between the virus’ low-profile outbreaks in Southeastern Asia (which took place in 2007 and 2012) and Zika’s explosive emergence in the Americas beginning in 2015.

“Our data offer a potential explanation for the recent re-emergence of ZIKV [Zika virus],” the authors conclude. And, they go on, the findings suggest that co-evolution between a virus and its vector—mosquitoes, in this case—is just as important for outbreak risk as co-evolution with its hosts—us.

Itching for data

Since Zika burst onto the scene in Brazil, researchers have been sifting through its genetics to figure out how it went from a relatively benign African virus, attracting little notice for decades, to a sudden international crisis, causing devastating birth defects. While researchers are working out all the ways the virus ravages the brains and bodies of developing babies , the authors of the Nature study wanted to figure out why the virus took off in Brazil when it did. After all, Zika was first discovered in 1947 (in Uganda’s Zika forest) and caused few noticeable outbreaks in the decades following.

The researchers, led by Pei-Yong Shi of the University of Texas Medical Branch and Gong Cheng of Beijing’s Tsinghua University, started off by comparing a Zika strain collected in 2010 with one from 2016. The 2010 strain was linked to the 2007 to 2012 outbreaks in Southeastern Asia, while the 2016 virus was linked to the strain circulating in the Americas at the time.

In experiments with mosquito-bitten, Zika-infected mice, the researchers quickly noticed that the 2016 virus was far better at infecting Aedes aegypti mosquitoes (a main Zika carrier) than the 2010 virus. The 2016 virus also produced much higher levels of a protein called “nonstructural protein 1,” or NS1.

NS1 is known to be critical to the virus’ spread. During an infection, virus-ridden cells secrete NS1, which then tours the body, fighting off immune responses. The researchers hypothesized that extra doses of NS1 in the blood of infected hosts helps overcome defenses in a feasting mosquito. This then allows the virus to settle in for a ride to a new host. The idea held up in experiments. When the researchers knocked back NS1 levels in blood using a special antibody, the virus wasn’t as good at hitching a ride. When they added NS1 to blood, the milder 2010 virus became a more frequent flier in the biting insects.

The researchers traced the boosted NS1 levels to a specific mutation in the gene that codes for the protein. The mutation—an alanine-to-valine amino acid substitution at residue 188 of the gene—was present in the explosive 2016 Zika virus but absent from its tamer 2010 relative. In cell experiments, the researchers found that this substitution mutation alone could switch NS1 levels from low to high. But they don’t know why, exactly.

Nevertheless, the researchers say the mutation may explain why Zika blazed through much of the Americas in the last few years and is now threatening to storm farther north. It's not definitive, of course, and the study doesn’t rule out the possibility that other factors—genetic or otherwise—sparked the devastating re-emergence. Researchers need more data to say for sure. But certainly, the authors note, “increases in the infectivity of mosquito-borne viruses within their vectors results in high epidemic potential.”

Nature, 2017. DOI: 10.1038/nature22365 (About DOIs).

This post has been updated to correct the institution of Pei-Yong Shi.