AsianScientist (Mar. 05, 2025) – Tucked away in the womb, a fetus is still vulnerable to viral infections passed from the mother—risking death or long-term health complications.
Now, a new study published in Cell, led by researchers from Duke-NUS Medical School at National University of Singapore (NUS), suggests that scientists may have been underestimating fetal immune systems all along.
“Early in pregnancy, a fetus cannot survive on its own and we have always assumed that it mostly relies on the mother’s immune system for protection against infections. However, we found that the fetus’ own immune system is already able to mount defenses against infections much earlier than previously thought,” said Ashley St John, an associate professor from the Programme in Emerging Infectious Diseases at Duke-NUS and lead author of the study.
St John and her colleagues wanted to take a closer look at fetal host responses and the ways they influence pregnancy outcomes. The study team included collaborators from NUS, Agency for Science, Technology and Research (A*STAR) in Singapore and Shanghai Jiao Tong University in China, among others.
For their study, they looked at the Zika virus transmission from mother to their fetus. Once transmitted, Zika virus can cause a multi-organ condition called congenital Zika syndrome (CZS) that endangers fetal development. Outbreaks in French Polynesia and Brazil coincided with a surge in babies born with microcephaly—a birth defect characterized by unusually small heads and underdeveloped brains.
Even so, many fetuses exposed to Zika virus survive despite neuronal damage and the signs of prior inflammation in their brains indicate that they can put up a fight.
Using a mouse model of CZS, the researchers selectively removed certain immune cell populations to learn how they each responded to infection.
They focused on microglia— immune cells that reside in the brain and shape its development by supporting the growth of neurons, clearing debris and pruning excess connections. In both mouse models and lab-grown mini brains called human brain organoids, microglia activated in response to Zika virus infection took on a protective role, helping to disrupt viral replication and limit neuroinflammation.
But immune responses of fetuses cane be harmful too. For example, monocytes contributed to brain damage. Monocytes are white blood cells, which appear later in development, infiltrated the fetal brain during infection and triggered harmful inflammation. This included driving up the expression of genes like Nos2, which are linked to the production of reactive oxygen species (ROS)—damaging molecules that kill neurons and disrupt their maturation.
When the mice were treated with an experimental anti-inflammatory drug that blocked Nos2 function, their condition improved. This suggested that targeting Nos2 could be a potential therapeutic strategy for Zika virus infections and other viral infections that cause brain inflammation.
“Our work has shown that the immune responses of fetuses can be either protective or harmful. Knowing how various immune cells contribute to fetal immune protection will be important in our continued search for ways to improve pregnancy outcomes,” St John said.
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Source: Duke-NUS Medical School ; Image: Freepik
The article can be found at Differential contributions of fetal mononuclear phagocytes to Zika virus neuroinvasion versus neuroprotection during congenital infection.
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