Severe flu during pregnancy compromises placental and brain barriers

A new mouse study from the University of Illinois Urbana-Champaign, published in Brain Behavior and Immunity, has discovered that severe influenza in pregnancy compromises placental and brain barriers in mice – allowing harmful molecules to reach the foetal brain. Due to the use of live viral exposure, the findings may translate to humans, highlighting the importance of vaccination. 

Placenta and brain barriers compromised 

“Our research indicates that the placenta and brain may be ‘leaky’ in utero, leading to downstream negative impacts on neural development and mental health outcomes,” said the study’s senior author Adrienne Antonson, assistant professor in the Department of Animal Sciences.

Previous studies showed that small molecules could pass through the placenta when pregnant mice were exposed to inactivated viruses. This study is the first to show placental breakdown with live influenza. It also demonstrated that fibrinogen – a molecule associated with neuroinflammatory conditions such as multiple sclerosis and Alzheimer’s disease – can infiltrate foetal brains.

Tracking the impact of influenza

Pregnant mice were infected with live influenza A virus at moderate and severe doses – simulating typical and extreme cases of human seasonal flu. At a stage equal to the end of the first trimester, the team injected the mice with fluorescent tracers of different molecular weights to track where these molecules accumulated in foetal tissues.

“We found that the largest tracers, which should not be able to get into the brain with an intact blood-brain barrier, accumulated in the foetal brain when the mums had severe influenza infections,” said the study’s first author, Rafael Gonzalez-Rincon, doctoral candidate in the Neuroscience Program in the College of Liberal Arts and Sciences at U. of I. “Tracers of all sizes also accumulated in the foetal liver and in the placenta for the severe infection group.”

Antonson added, “The placenta has really only become a focus in this field in the last five to ten years. Historically, developmental neuroscientists haven’t considered the placenta in their day-to-day work. We wanted to shed some light on the placenta to show that we can’t discount its importance in modulating foetal brain development, and our data back that up. The fact that large molecule tracers got through could be quite significant.”

Fibrinogen: a potential threat to foetal brains

In a separate experiment, the team investigated whether fibrinogen could accumulate in foetal brains. Normally involved in blood clotting and early pregnancy, fibrinogen can be harmful when it enters the brain.

“When this molecule gets inside the brain, it has been shown to trigger the production of reactive oxygen species and increase the oxidative state in general,” Gonzalez-Rincon said. “That can lead to damage to developing neurons as well as cell death.”

The researchers found fibrinogen accumulation in the foetal brains of mice with severe influenza. Both fibrinogen and large  tracer molecules concentrated in the subventricular zone and choroid plexus, suggesting vulnerability of the blood-brain and blood-cerebrospinal fluid barriers during prenatal infection.

“Stem cells in the subventricular zone differentiate into radial glial cells and into neurons,” Gonzalez-Rincon said. “They are critical for neurodevelopment. We hypothesise that if those cells are exposed to an inflammatory state, that can affect normal brain trajectories.”

Implications for human health

Although the study was conducted in mice, Antonson notes the findings are more relevant to humans than ever before, due to the use of live viral exposure.

“The unique feature of including the moderately pathogenic dose and the severely pathogenic doses of live influenza virus actually mirrors features in epidemiological human data as well. Not every pregnant woman who is exposed to a virus is guaranteed to have a child who has neurodevelopmental difficulties. When we compare those doses, our results really help confirm the idea that there’s an infection or pathology severity threshold, where you need to get sick enough before these things to really take hold. In pregnant people, getting a flu shot can reduce severe outcomes, so please get vaccinated,” she said.

The findings from this study highlight the critical role of the placenta in protecting foetal brain development and demonstrates how severe maternal influenza can compromise that protection. The results also reinforce the importance of preventing serious flu infections during pregnancy through vaccination.