Researchers at Duke and Mt. The Sinai have identified a molecular mechanism that prevents viral infection during a mother's pregnancy from harming her unborn child.
When a person becomes infected with a virus, their immune system sends out a chemical signal called type I interferon, which tells surrounding cells to increase their antiviral defenses, including increased inflammation.
This reaction prevents the virus from copying itself and gives the adaptive immune system more time to familiarize itself with the new invader and hunt it down.
A pregnant woman who comes across a virus will generate the same signals to protect herself. However, if these signaling molecules and the resulting inflammation could cross the placenta and reach the fetus, they would lead to serious developmental disorders and even death of the fetus.
However, this generally does not happen, with the exception of the Zika virus and a handful of other viruses that are known to replicate and harm the fetus. (Despite nearly 100 million reported cases of COVID-19 around the world, there is no clear evidence that the virus that causes the disease, SARS-CoV-2, poses a threat to fetuses.)
The research team found a mechanism that protects the fetus from the damage that the mother's immune response to a virus could cause. In an article dated January 15 in scienceThey identify a key player on this path as an estrogen receptor on the cell surface called GPER1, which is particularly common in the placenta and fetal tissue.
"This probably explains why many maternal infections do not harm the fetus during pregnancy," said study director Nicholas Heaton, assistant professor of molecular genetics and microbiology at the Duke School of Medicine.
After finding GPER1 as a possible candidate for this effect through a series of screenings, the researchers found GPER1 receptors concentrated in the placenta, where the mother's blood supply carries oxygen and nutrients to the fetus. Estrogen levels are much higher during pregnancy, which allows the GPER1 receptor to suppress interferon signals in the placenta and the developing fetus even better.
The researchers tried to block this particular estrogen receptor in pregnant mice with a compound called G15. They found changes in the placenta during influenza A virus infection or G15 treatment that resulted in slightly smaller mouse pups. But with both G15 and influenza virus, the pups were dramatically smaller and many were stillborn.
They also tested mouse pregnancies with Zika and influenza B virus infections and found that the addition of the G15 treatment again resulted in many more fetal defects.
"If we turn off the GPER1 pathway, even normally benign maternal infections (like the flu) are now causing major fetal development problems," Heaton said.
Heaton calls it a way because his team doesn't yet understand how GPER1 provides that protection. They suspect that the receptor triggers other downstream mechanisms that come into play.
Heaton said the beauty of this system, centered around the baby, is that it protects the fetus from inflammation while the rest of the mother's tissues are better able to use interferon to fight the virus.
The researchers will next test whether "hyperactivation" of the GPER1 signaling pathway is a way to protect the development of the fetus when a mother becomes virally infected.
This research was supported by the National Institutes of Health, the National Institute of Allergy and Infectious Disease, the National Heart, Lung and Blood Institute, and the Hartwell Foundation. (Permit numbers T32-CA009111, T32-AI07647, R21AI139593, R21AI144844, R01AI37031, R01HL142985)
QUOTE: "GPER1 is needed to protect fetus health from maternal inflammation," Alfred Harding, Marisa Goff, Heather Froggatt, Jean Lim and Nicholas Heaton. scienceJanuary 15, 2021. DOI: 10.1126 / science.aba9001