“Basically they found that these [related] viruses were able to cross the placenta and infect the developing fetus,” says microbiologist Jean Lim of the Icahn School of Medicine at Mount Sinai in New York who was not involved in the project. “The study is provocative because it highlights the need to evaluate how other flaviviruses, such as West Nile, may affect the baby.”
Following the 2015 outbreak of Zika infections in Brazil and surrounding countries, it quickly became apparent that the virus could cause microcephaly—a smaller than normal head—and other abnormalities in babies born to infected mothers.
Zika was originally identified in 1952 and not previously linked to microcephaly, so “there had been a lot of speculation about Zika virus being unique . . . that it had evolved,” says immunologist and microbiologist Jonathan Miner of Washington University in St. Louis who led the study. “But I’m very skeptical.” For one thing, “the medical literature doesn’t point to that,” he continues, citing sporadic case reports of pregnant women infected with West Nile virus who had babies with birth defects.
Another possibility for Zika’s new-found link to microcephaly, Miner says, is the shear scale of the recent outbreak. Because the incidence of microcephaly compared with that of infection is low, explains Miner, in previous, smaller outbreaks the link may simply have been overlooked. If this is the case, then it’s entirely plausible that other related flaviviruses with similar modes of human infection may also occasionally cause birth defects.
To investigate this possibility, Miner and colleagues chose to examine two related flaviviruses: West Nile virus, which like Zika is transmitted by mosquitoes, and Powassan virus, an emerging tick-borne virus spreading through the northeastern U.S. Both viruses are capable of causing brain inflammation in severe cases of disease, suggesting that, like Zika, they have a tendency for targeting the nervous system. The team also examined two unrelated mosquito-borne alphaviruses: chikungunya and Mayaro, both of which can also cause encephalitis in adults.
The researchers infected pregnant mice with the viruses—each mouse receiving one of the four types—via injection just under the animal’s skin “to mimic an insect bite,” Miner says. Then, they waited a week or two. When the researchers examined the placentas and fetuses, all of them had viral RNA. But, by far, the largest amounts were found in mice infected with West Nile virus. In contrast, the mothers had comparable viral RNA levels regardless of the injected virus they received. Furthermore, approximately 50 percent of fetuses from the animals infected with either West Nile or Powassan virus died as a result of the infection, while no fetuses died as a result of maternal alphavirus infection.
Close inspection of organs and tissues from some of the fetuses revealed that, in the case of West Nile infections, a range of mild to severe brain damage had occurred.
The team went on to examine how the viruses behaved in mid-gestational placental tissue samples (maternal and fetal) from human donors. They found that while Powassan and West Nile virus replicated readily in all samples, the alphaviruses exhibited inconsistent and less abundant replication.
“These findings are interesting because they suggest Zika may not be unique,” says Lim. In particular, “West Nile virus, which is the most important pathogen for the United States, could negatively impact the developing fetus in a very small subset of pregnant women.”
Alarming as the results may seem, “we’re talking about mice, and about human placental explants, so I think we have to be careful about how much we generalize the outcomes to the human experience,” says microbiologist and immunologist Stephen Thomas from SUNY Upstate Medical University who did not participate in the research. Still, he adds, the study certainly serves as “yet another call to action for anyone involved in the research and development of [flavivirus] countermeasures, whether they be vaccines or drugs.”
D.J. Platt et al., “Zika virus–related neurotropic flaviviruses infect human placental explants and cause fetal demise in mice,” Sci Transl Med, doi:10.1126/scitranslmed.aao7090, 2018.