A New Study Investigates How Flu Infection During Pregnancy Impacts Developing Babies’ Brains

By Ananya Dash

Influenza or flu infection in pregnant women can be worrisome for the unborn baby. Population level studies show a higher incidence of neurodevelopmental disorders in the babies of women who developed flu while pregnant. 

A new study published in July in Molecular Psychiatry, conducted in mice, provides evidence that the extent of flu infection in pregnant women decides their baby’s brain development. The result shows that the severity of flu infection in pregnant women alters the trajectory of babies’ brain development inside the womb, especially in regions of the brain, critical for learning and memory.  

Researchers at the University of Illinois Urbana-Champaigne infected pregnant mice with a moderate and severe dose of flu virus. Their goal was to mimic varying levels of seasonal flu infections observed in humans. “Not everyone gets a severe flu infection,” says Adrienne Antonson, PhD, an assistant professor in the Department of Animal Sciences at University of Illinois Urbana-Champaigne and the lead author of the new study. “We use two different doses to be able to replicate seasonal responses as best as we can.” 

Infecting pregnant mice with flu virus seems to be a straightforward strategy, but scientists rely on using parts of flu viruses, such as their genetic material, to mirror an infection for two reasons. First,  flu virus does not cross the placenta, the organ that transfers nutrients and waste between the mother and developing baby, and so cannot affect the brain. It is, rather, the mother’s immune response to flu infection that triggers the brain defects in babies. Second, unlike humans, mice are not natural hosts of flu viruses. Hence, creating imitation viruses, or viral mimics, serve as powerful tools with their ability to trigger the immune system of the mother.  

Antonson planned to use viral mimics for her work, but a chance meeting with a virologist changed her approach. The virologist taught her how to engineer flu viruses to naturally infect mice, using the whole pathogen rather than parts of it. Antonson and her team repeatedly exposed the mice to this engineered flu virus, passing it from one animal to another, reflective of how infections spread from person to person.

The group’s novel approach enabled them to take a deeper dive into the mother’s immune response.  “There is a consequence to viral load to immune response that is ignored many times,” says Seema Lakdawala, PhD, an associate professor of microbiology and immunology at Emory University.

Every infection brings two waves of immune responses, she adds. The first one is non-specific and begins within a few minutes to hours of the infection, called the innate response. The second one is specific and happens after a few days, called the adaptive response. The outcome of an infection is dependent on how the virus takes over the immune system. Flu infection can capture the spectrum of immune responses that viral mimics cannot.  

Flu infection in pregnant mice led the team into an uncharted territory as their approach has not been used before. Antonson’s team looked for the obvious signs of infections – loss of weight and lung damage in pregnant mice to ensure their infection led to symptoms. The decline in weight was more pronounced in pregnant mice who received a higher dose of flu than the ones who received a lower dose.  

IL-17, a signaling molecule with inflammatory effects, can cause brain abnormalities in babies when pregnant mice are infected with viral mimics. In this study, however, there was no difference in IL-17 levels between the blood of infected and uninfected mice. Ashley Otero, the first author of the study expected that they may not observe any brain defects at this juncture, given that there was no increase in IL-17 in pregnant mice. Otero’s experiments were about to tell otherwise.  

The study revealed that the thickness of the cortex, the outermost layer of the brain responsible for cognitive functions such as learning and memory, was reduced significantly in the brains of developing babies’ only when their mother had severe flu. This led the team to their next question: where do inflammatory signals originate in babies’ brain?  

They discovered the quantity of border-associated macrophages, immune cells bordering the brain to protect it from foreign substances, was significantly higher in the babies’ brain if their mother had severe flu. These macrophages, in excess, can attack neurons instead of protecting them, possibly reacting to the inflammatory signals sent by the mother’s immune system.

This result echoes earlier work published in 2020 in Developmental Cell, which found that greater macrophage population affects the developing brain negatively. In that study, scientists used viral mimics in pregnant mice to induce the mother’s immune system. In turn, they found that the babies’ brains were inundated with macrophages that was harmful to proper brain growth.  

Extrapolation of mice studies to humans is still challenging. Flu infections last for about a week during pregnancy in humans, a fraction of the nine months. Mice are pregnant for about 20 days and the infection with flu viruses last for a considerable part of their pregnancy. “It is more accurate way to say that severe infections and stress within the mother can have consequences and implications on the fetus,” Lakdawala says.

This study, overall, points out that only severe flu infections can impact brain development in the babies. “The best thing that a woman can do, is, number one, be informed, but number two, get vaccinated,” Antonson says. “When mom gets vaccinated and she generates neutralizing antibodies, she passes those through the placenta on to her offspring, and so she’s immunizing her child when she gets immunized.”

The approach of infecting mice with flu virus that mimics seasonal flu strains in humans is a major advancement for the field. This system will enable Antonson and scientists in the field to study the interplay of virus and mother’s immune system on a baby’s brain development. Further, there many variables that can define brain development. Antonson hopes to expand her research to understand how infections change mother’s microbes and placenta, in addition to the immune response, to impact brain development.