A severe case of flu during pregnancy can increase the risk of fetal neurodevelopmental disorders such as schizophrenia and autism spectrum disorder. But it’s not the virus itself that does the damage; it is the mother’s immune response.
New Urbana-Champaign research from the University of Illinois, using live, mouse-adapted influenza virus, improves on previous mouse experiments to explain the process at the cellular and molecular level. It also indicates that changes in the fetal brain are more likely once the severity of the mother’s infection reaches a specific threshold.
“Our data provides really compelling evidence for an infection severity threshold that is similar to what we see in humans. There is only a subset of maternal infections that will be serious enough to cause this type of concern. That said, pregnant people should definitely get the flu vaccine to reduce their risk,” said senior study author Adrienne Antonson, assistant professor in the Department of Animal Sciences, part of the College of Agricultural, Consumer and Environmental Sciences at Illinois.
The study is one of the few to examine maternal infection in mice using live influenza virus at doses that mimic seasonal flu outbreaks in humans. “That means our results are more relevant to human pathological infections,” said lead study author Ashley Otero, a doctoral student in the Neuroscience Program at Illinois.
Antonson’s team infected pregnant mice with live influenza A virus, instead of a viral mimic – an inert molecule that mimics viral behavior – used by most research groups in recent decades. The viral mimic induces the innate immune response, broadly categorized as nonspecific inflammation, which occurs within 24 to 48 hours of infection.
These studies have provided important clues about which inflammatory proteins are made by the mother and how they interact with the fetal brain. But Otero says viral mimics can trigger slightly different immune responses than the live virus in both mother and fetus, and they fail to capture what happens during the mother’s adaptive immune response, which kicks in later and helps an animal avoid infections to ‘remember’ from the past.
To address these issues, the team subjected the mice to one of two doses of the virus – representing a moderate or severe infection – at the time of pregnancy closest to the end of the first trimester in humans is. They then monitored two and seven days after infection to see how the infection developed in the mother’s lungs and intestines, and how products of the mother’s immune response interacted with the fetus’ brain. They also measured the physical properties of fetal brains, including the thickness of the cortex, which has been linked to neurodevelopmental disorders in humans.
Several important viral mimicry studies in mice have implicated an immune protein called interleukin-17 – produced mainly by T helper (Th)-17 cells in the mother’s intestinal tract – in changes in the fetal brain and neurodevelopmental disorders after birth. . But the live virus did not activate that protein.
“When I initially saw that interleukin-17 was not elevated in our mothers due to influenza infection, I was confident that we would not see any changes in the developing fetal brain,” Otero said. “But interestingly, we saw very similar responses in the developing neocortex, including dramatic reductions in the upper neuronal layers in fetuses born to mothers who had the higher dose of infection.”
Otero further explains that human postmortem studies have documented smaller cortical structures in people with schizophrenia and autism spectrum disorder. “So our results really matched what we see in human brains.”
Antonson added: ‘We don’t think it will ever be just one inflammatory molecule that causes all these different things. But this is the first time that this pathway has been thoroughly investigated and compared to models that have so far shown that interleukin -17 is really involved. Therefore, it is important to move beyond viral mimicry models to the real live virus.”
After ruling out interleukin-17, at least at the time points they studied, the team tracked immune cells in the fetus’ brain. Microglia, which infiltrate the brain and interact with developing neurons, showed signs of increased inflammatory activity in fetuses born to high-dose influenza-infected mothers. Fetal border-associated macrophages (BAMs), which border brain surfaces and provide constant immune surveillance, were also more active and abundant. Both cell types normally help with healthy brain development, but Otero and Antonson think that when they are put into an overactive state, they can attack healthy developing neurons instead of supporting them.
Viral mimicry studies have also implicated overactive microglia in causing fetal brain malformations, but BAM activity is vastly understudied. Otero plans to conduct more research to understand the role of BAMs in prenatal flu infections.
Antonson emphasizes that maternal infection is only one of many risk factors for neurodevelopmental disorders.
“These conditions are caused by a multitude of elements, including environmental factors, genetics, pharmacological exposures and more. We’re just focusing on this in-utero period, but the early postnatal period is important, and adolescence is important. a piece of a very complicated pie.”
The research was supported by the Roy J. Carver Charitable Trust (grant #23-5683), USDA NIFA Research Capacity Fund (Hatch project #ILLU-538-940), the Department of Animal Sciences, and the College of ACES.
Antonson is also affiliated with the Beckman Institute, the Mbiotic Systems Initiative and the Carl R. Woese Institute for Genomic Biology in Illinois.
