To understand how Zika shrinks a baby’s brain, scientists look to other viruses
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Pregnant women across Latin America and the Caribbean are now fearful of the Zika virus and the effects it might have on their fetuses’ brains. But when it comes to viruses that cause birth defects, Zika is hardly alone.

Rubella, herpes, cytomegalovirus — all these pathogens can cause microcephaly, which leaves newborns with abnormally shrunken heads and malformed brains. And scientific sleuths are now looking to these other viruses for clues to explain how Zika might be attacking the budding brain, and, if so, how to stop it.

In developed countries, a vaccine has all but eliminated rubella (also known as German measles), but no proven vaccine exists for CMV, a virus that’s spread through close contact with bodily fluids. Most people infected with CMV don’t even know they have it because, like Zika, it rarely causes symptoms in healthy adults. But developing fetuses are another story.

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If a woman contracts CMV for the first time while pregnant, she has an estimated 35 to 50 percent chance of passing the virus to her fetus, and 1 in 5 babies born with CMV suffer birth defects. It is the leading viral cause of microcephaly.

Viruses like CMV generally need to infect the fetus itself if they are going to interfere with its maturation. First, though, they have to get across a barrier imposed by the placenta — and only certain viruses have the knowhow to find a passage.

Sometimes viruses have the right keys to unlock placental cells directly. Or they can sneak across the surface by hooking onto the antibodies that are passed from mother to child.

Alex Hogan/STAT Are you at risk for contracting Zika virus? Your level of risk depends in part on your living conditions.

But according to Dr. Laura Gibson, an infectious disease specialist at the University of Massachusetts Medical School, the method of “riding on the coattails of an antibody” to invade the fetal side tends to occur later in pregnancy, when the baby is rapidly swallowing up maternal antibodies to build up its own immune system.

And the sooner in pregnancy CMV reaches the fetal brain — particularly during the first or early second trimester — the more extensive damage it appears to wreak.

With Zika, case studies have similarly associated early infection with more dramatic fetal problems, although researchers are still trying to show a causative relationship between Zika and microcephaly.

“It’s following the pattern that’s seen with other infections,” said Dr. Sharone Green, a virus expert at UMass Medical School.

So how does CMV get in early? Researchers think the virus homes in on a type of placental cell called a cytotrophoblast, which comes into direct contact with the mom’s blood and cells rich with virus. For CMV then, it’s a short journey over to the fetus’s side.

CMV can infect different fetal tissues, but researchers think it appears to target nerve cells in particular — which is what initial studies of Zika have shown, too.

On Friday, scientists working with human cells in the laboratory reported in the journal Cell Stem Cell that Zika can infect and kill a type of neural precursor cell that’s essential for building a functioning brain. The virus also replicates inside the cells, setting off a chain reaction of infection.

Dr. Guo-li Ming, a senior author of the study, said the results showed Zika puts a bull’s-eye on certain neural cells, meaning any damage in the brain is likely a direct result of infection, not a side effect, although further studies in animal models and people are needed to confirm this.

“If you think about microcephaly, that’s a profound congenital birth defect,” said Ming, a neuroscientist at the Johns Hopkins School of Medicine. “We thought it had to be targeting cells during early neurodevelopment.”

CMV also appears to kill off a type of neural stem cell, albeit a different one. Experts believe the virus dismantles the scaffolding that directs new neurons where to travel, throwing the organization of the forming brain into disarray.

“Nerve cells are generated deep in the brain,” said Dr. William Dobyns, a pediatric neurologist at Seattle Children’s Hospital. From there, the neurons climb that scaffolding to their designated positions in the cerebral cortex. But “if the scaffolding is destroyed, they’re going to have a problem climbing,” Dobyns said.

The hopscotch CMV completes to go from the mother’s cells to the fetal side can take six to eight weeks. That length of time has opened the door to the hope that treating the mother with antibodies that could slow CMV before it reaches the fetus, although studies haven’t conclusively found that the approach works.

If Zika follows a similar timetable, experts say, then perhaps Zika-fighting antibodies could be given to pregnant women infected with the virus to stop it from moving from mom to baby.

“The aim is to understand what antibodies would be the best way to treat a woman, or what antiviral approaches you would use in this time,” said Lenore Pereira, a molecular virologist at the University of California, San Francisco.

The reason scientists are looking so hard at CMV, a type of herpesvirus, is that, among the family of mosquito-borne “flaviviruses” — which include yellow fever, Japanese encephalitis, dengue, and West Nile — only Zika seems to have the capacity to incur damage on fetal development with some regularity.

“In no way when we talk about congenital infections that cause problems for newborns do flaviviruses come in as a common cause,” said Dr. Susan McLellan, an infectious disease and tropical medicine expert at Tulane University. “What’s going on with Zika seems to be very, very different.”

A lingering question is what role past viral outbreaks in areas hit hard by Zika play. It’s just a theory at this point, but some wonder whether the spread of dengue in Latin America in recent years may intensify the effects of Zika, making it more likely that it raises the risk of microcephaly.

“Who knows how prior flavivirus exposure manifests in acute Zika infection?” said Dr. Desiree LaBeaud, who studies mosquito-borne viral infections at Stanford University. “We don’t know if it protects, we don’t know if it puts you at more risk.”

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