It remains one of the great mysteries of the Zika epidemic: Why did a virus that existed for decades elsewhere in the world suddenly seem to become more destructive when it landed in Latin America?
Why did the Zika virus cause thousands of babies to be born with microcephaly, unusually small and damaged brains, when previous outbreaks in Africa and Asia seemed to cause much less harm?
An intriguing study in mice, which has prompted some skepticism among experts, suggests that a single genetic mutation helped transform the Zika virus into a devastating force in Latin America. The report was published on Thursday in the journal Science.
The mutation, called S139N, first arose in an Asian strain of the Zika virus in 2013, just before a small outbreak in French Polynesia — the first linked to an increase in babies born with microcephaly.
Zika is believed to have first appeared in Latin America later in 2013, possibly introduced by soccer players from French Polynesia competing in a tournament in northeastern Brazil. The mutation has appeared in every strain of the virus in the Latin American outbreak, the researchers said.
The study, by scientists in China, found that strains of Zika with the S139N mutation caused substantially more death and microcephaly in mice than other strains. And in a laboratory dish, the S139N strain killed many more human cells important to early brain development than an earlier strain without the mutation.
Some experts voiced doubts, saying the findings were too preliminary to establish that a single mutation was the critical factor. At least, they said (and the study authors agree), the results must be replicated in primates, because laboratory experiments with mice and even human brain cells cannot fully capture how the virus functions in nature.
“It’s potentially important, and it’s provocative,” said David H. O’Connor, head of global infectious diseases at the University of Wisconsin-Madison’s primate center, which has tested the Zika virus in monkeys.
“But it will require a lot of additional work to show that it can be reproduced in multiple settings, to show that it isn’t simply a coincidence.”
Other experts found the study persuasive.
“They showed this mutation is both sufficient and necessary to make the virus worse,” said Hongjun Song, a neuroscientist at the University of Pennsylvania who helped discover how Zika attacks the fetal brain. “I would say this is one of the smoking guns.”
“The scary part, maybe the take-home message, is that it doesn’t take that much — just one mutation — to make something really, really bad,” he added.
The researchers do not claim the S139N mutation is solely responsible for the birth defects among children born to women infected by mosquitoes during pregnancy. Other causes could involve differences in the population in Latin America, including the possibilities that their genetic makeup or exposure to previous mosquito-borne viruses made them more susceptible to harm from Zika.
It is also possible that Zika previously caused microcephaly, but cases simply went unnoticed when the virus reached Asia around the 1960s.
Microcephaly has many causes, many mothers gave birth at home, and newborns with severe brain damage might have died without immediate intensive care. The surge in microcephaly in northeast Brazil in late 2015 was noticed by doctors in hospital neonatal units.
The researchers noted that strains of the virus without the S139N mutation caused some mice to develop mild microcephaly, meaning that the mutation, which occurs on a protein involved in making the virus’s protective coating, is likely only a piece of the puzzle.
But it seems to be an important piece, the scientists said.
“In the beginning, we thought we may need multiple mutations” to create a viral strain that causes severe microcephaly, said Dr. Zhiheng Xu, a principal investigator with the Institute of Genetics and Developmental Biology at the Chinese Academy of Sciences, who led the study with Cheng-Feng Qin, a virologist at the Beijing Institute of Microbiology and Epidemiology.
“That was a surprise to us, that it was just one mutation.”
The researchers first compared a strain of the Zika virus from an outbreak in 2010 in Cambodia with three strains from the recent Latin American outbreak. The viruses were injected into brains of one-day-old mice whose development, the researchers said, approximates that of third-trimester human fetuses.
About 17 percent of mice infected with the Cambodian strain died, compared to 100 percent of mice infected with the Latin American strains.
Next, the researchers created a Zika virus with several of the seven mutations that have appeared since 2013 and found that it caused greater mortality in newborn mice than the Cambodian strain. Then the team made seven strains of the Zika virus, each with one mutation.
Six caused comparatively mild damage, similar to the Cambodian strain. But the virus with the S139N mutation — in which only one nucleotide differs from the Cambodian version — killed more mice and caused more brain damage. In mouse embryos, the S139N mutation caused more severe microcephaly and dead brain cells.
To double-check the finding, the researchers created yet another strain, this one with a reversed version of the mutation: N139S. Its effect on mice was mild, like the Cambodian strain.
Even then, Dr. Qin was “not quite confident about the significance of our finding,” he said. “Honestly, we are also asking ourselves, ‘Can these results directly translate to humans?’”
So they tested the strains on human neural progenitor cells, which act as scaffolding upon which the fetal brain forms and are the virus’s main target. The S139N strain reproduced faster than the Cambodian strain and killed more cells.
The authors and other experts said they did not know why the mutation might have such a profound effect.
The viral coating protein that contains the S139N mutation is “used in viral assembly” before part of the protein degrades, said Genhong Cheng, a microbiologist at the University of California, Los Angeles, who was not involved in the study.
So S139N may make the coating more protective or help the virus assemble more effectively, he said. “It certainly seems like this particular mutation is able to at least make a contribution to making it more virulent,” Dr. Cheng added.
Still, recent microcephaly cases in Thailand were caused by an Asian strain without S139N, he noted, so it is unlikely to be the only villain.
Kristian G. Andersen, director of infectious disease genomics at the Scripps Research Institute, said the study had several important limitations, including that it did not explain why, in the recent outbreak, microcephaly rates varied widely across the Americas.
Microcephaly cases were heavily concentrated in northeastern Brazil, for example, but the mutated Zika strain was found everywhere.
“This is an interesting study, but I’m skeptical of their findings, and I don’t believe their hypotheses are well supported,” he said.
Dr. O’Connor noted that injecting the virus directly into mouse brains did not mimic infection in nature, where the virus must infect a mother, cross the placenta and reach the fetus.
The researchers also did not try to address why this mutation might have persisted. Did it confer a survival advantage to the Zika virus or just incidentally increase the virus’s ability to cause microcephaly?
“That’s a very good question,” Dr. Xu said. “You got me.”