Most adults don’t even notice a Zika virus infection, and those who do typically feel just aches, a fever or a mild rash. What makes the virus terrifying is what it does to its youngest victims — the fetus — which may suffer severe neurological damage, microcephaly and death.
Of the myriad viruses that plague human beings, only a handful can invade the placenta to reach a growing fetus, where the resulting infections can restrict fetal growth or trigger spontaneous abortions or preterm labor. They include Zika, rubella (the virus that causes German measles) and cytomegalovirus, or CMV (which lurks in at least 7 of 10 adults).
How these viruses manage to reach the fetus has been a puzzle, says molecular virologist Lenore Pereira of the University of California, San Francisco. Generally, the fetus is well-protected even though pregnancy creates an immunological paradox — half of a fetus’ genes come from the father, so the fetus itself should be perceived as foreign. Rejection doesn’t happen because the mother’s body has immune-suppressing mechanisms that allow the placenta to establish itself.
And the placenta itself — a disc-shaped organ that starts as a single cell and grows to a one-pound structure that nourishes and protects a growing fetus — has potent ways to block maternal cells, proteins and most pathogens, viral or other, from crossing the maternal-fetal barrier. The mature placenta has two halves: one that originates from the embryo, the other from the mother’s uterine tissue. Each side is filled with an intricate mesh of blood vessels to shuttle nutrients and oxygen from mom to growing fetus, and each harbors protections from pathogens.
New studies of this maternal-fetal layer are helping to explain how certain viruses manage to make the jump, Pereira writes in the Annual Review of Virology . The reasons, she tells Knowable, lie as much in a mother’s body as in the pathogens themselves. This interview has been edited for length and clarity.
How did you get into researching these problematic viruses?
At the peak of the AIDS epidemic, we were very interested in understanding how CMV infected cells of the retina. AIDS patients could go blind because of these infections. That’s how we began to study specialized cells known as polarized epithelial cells — which have distinct top, bottom and sides — in the retina. We found that the virus uses different receptors to get in, different pathways to travel across the cell and others to enter adjacent cells on either side.
As antiviral drugs to AIDS became more available, there was less interest in the pathology of this virus in retinitis because these infections didn’t happen anymore.
At that point, we knew a lot about polarized cells, which also form the placenta. So we turned to the problem of how a virus gets across the placenta.
Are these cells the same in the placenta and the retina?
They’re both polarized cells. But what these cells do in the placenta is different from what they do in the eye. They’re basically the placenta’s building blocks. Early in gestation, they proliferate and invade the uterine wall, like a little army. They work as a team to make the right chemicals and proteins that will allow them to bore their way in and degrade the uterine wall. It’s a very inflammatory process. But the mother doesn’t even know it. She’s probably just thinking, “Oh, I don’t feel so well” because of morning sickness. (We don’t know of any connection between these chemicals and morning sickness, though.)
How does the placenta change over the course of a pregnancy?
In the first trimester, it’s establishing itself and growing. Once the placental cells get into the uterine wall, they encounter the mother’s blood vessels and break them open. The placenta gets rid of the teeny, tiny little arteries that are usually there and creates a huge new one, which is kind of like a tunnel. That’s how the mom’s blood flow reaches the surface of the placenta.
By mid-gestation, the placenta has remodeled all the uterine arteries it’s going to, and about a liter of blood per minute is pouring onto the surface of the placenta. The mom’s blood never actually reaches or touches the baby — only the placenta. Anything that the baby needs has to be transferred across the placenta, so the placenta needs to be fully functional for everything to go normally.
In the second half of a pregnancy, the placenta just gets bigger and bigger. The most important change in late gestation is that maternal antibodies can reach the fetal blood stream by passing through a layer of cells in the placenta. These are the antibodies that the baby has for the first six months of its life.
Everything has got to be just right for the placenta to develop properly. If a virus infection changes that in any way, then you predispose the fetus to poor growth.
How does the immune system protect the placenta and fetus during this process?
The pregnant uterus is very unusual. It produces immune chemicals known as cytokines that act like attractants — calling in a repertoire of immune cells to the uterus and mother’s side of the placenta that will protect the fetus from infection. You can’t have the usual groups of killer T cells within the placenta because they will attack the placenta and baby, so there’s a sort of “soft” immune defense that reduces levels of pathogens but can’t necessarily eliminate them.
It’s not an immune system per se, but the placenta contains a whole network of macrophages — white blood cells that engulf viruses and other pathogens. Also, tissues are continually formed and broken down as the placenta grows and builds the umbilical cord. The macrophages migrate throughout the maternal side of the placenta to clear dead cells. On the fetal side, protection is from a special kind of macrophage known as Hofbauer cells, made by the fetus. They do the same thing as macrophages on the mother’s side.
Can a lot of viruses get past these defenses?
There are very few viruses that can cross the placenta and get to the baby. First, they must be carried by blood, either as free-floating particles or inside blood cells. Lots of viruses are carried by blood, but not all.
But the virus also has to remain circulating in the mom’s blood for some time. Then it has to make the right proteins that enable it to bind to placental receptors. And because the placenta is maturing, it doesn’t keep the same receptors throughout the pregnancy.
So the virus has to be in the right place, in huge amounts, at this critical time when the placental cells are making the right receptor. And it should not be killed by mom’s macrophages or degraded by Hofbauer cells. Everything has to be just right for a virus to grow in the placenta.
How do some, like CMV or Zika, subvert these defenses to cause infection?
These two viruses target the placental cells, enabling them to get across into the fetal bloodstream, though in slightly different ways.
Both infect the mother’s monocytes, a certain kind of immune cell. The uterus is spewing out chemoattractant proteins, and these cells are responding by traveling to the uterus to protect the baby from infection. Except that some of them are infected with CMV or Zika.
In the case of CMV, the virus is dormant inside the monocytes but is probably reactivated once it’s inside the inflammatory environment of the uterus. The hypothesis is that the virus grows in the monocyte that brought it in and then — if it’s not cleared by the immune cells around — is transferred to uterus and placental cells, to reach the fetus. This hasn’t been formally shown yet.
Zika, on the other hand, is already active. It is released from an infected cell and then infects others, including placental cells that contact the fetal bloodstream. It can very quickly — and very early — reach fetal blood inside the developing placenta.
The two viruses are quite different from each other. But they are both in the same place, sometimes at the same time, and they have an environment that really allows them to grow.
It’s just an unfortunate result of how the natural development of the placenta takes place, creating an environment where the virus can grow, where ordinarily, it wouldn’t.
What’s the eventual goal of learning how these viruses infect fetuses?
It’s important to understand the virus life cycle and what the mother is making antibodies to, meaning which viral proteins are the targets of those antibodies.
If we can understand, we can better design vaccines. I’ve always been interested in the medical aspects of what we do — not only the molecular benchwork, but how to make it applicable to solving problems of human infection in women and their babies.