URBANA, Ill. — A new study from the University of Illinois Urbana-Champaign shows, for the first time, that severe flu infection in pregnant mice leads to a breakdown in placental and brain barriers, leading to the accumulation of potentially harmful molecules in the fetal brain.
"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 , part of the College of Agricultural, Consumer and Environmental Sciences at Illinois.
Previous studies have shown that certain small molecules can pass through the placenta when pregnant mice were exposed to pathogen mimics or inactivated viruses, but this is the first time the breakdown in placental function has been shown with a live influenza virus. It's also the first time researchers have shown that fibrinogen — a multi-function molecule correlated with neuroinflammatory conditions such as multiple sclerosis, Alzheimer's Disease, and traumatic brain injury — can pass into developing fetal brains.
The research team infected pregnant mice with live influenza A virus at moderate or severe levels, simulating typical and extreme cases of seasonal flu in humans. At the stage of pregnancy approximating the end of the first trimester, the researchers intravenously injected anesthetized pregnant mice with fluorescent tracers of different molecular weights. These allowed the researchers to track exactly where the tracers — which mimic various sizes of abundant blood proteins — ended up in the fetal tissue.
"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 fetal brain when the moms 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. and member of Antonson's research group. "Tracers of all sizes also accumulated in the fetal 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 fetal brain development, and our data back that up. The fact that large molecule tracers got through could be quite significant."
Next, in a separate group of flu-infected pregnant mice, the researchers looked for fibrinogen accumulation in fetal brains. Fibrinogen has multiple functions in the body, mostly related to coagulation. For example, it is involved in blood clotting when a vessel breaks. It is also abundant during the early stages of pregnancy, when the endometrium attaches to the uterine wall. When it appears in the brain, however, it tends to cause problems.
"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."
In adult humans and mice, fibrinogen accumulation in the brain has been documented in multiple neurodegenerative conditions. Nothing was known about its impact on fetal brains so far, but Gonzalez-Rincon, Antonson, and their collaborators found that fibrinogen accumulated in fetal brains of pregnant mice with severe influenza A infection.
Both the fibrinogen and the high molecular-weight tracers accumulated in the subventricular zone and choroid plexus in fetal brains, suggesting the blood-brain and blood-cerebral spinal fluid (CSF) barriers are particularly leaky in those regions during a prenatal influenza infection.
"Stem cells in the subventricular zone differentiate into radial glial cells and into neurons," Gonzalez-Rincon said. "They are critical for neurodevelopment. We hypothesize that if those cells are exposed to an inflammatory state, that can affect normal brain trajectories."
Although the study was done in mice and is just the first among many pre-clinical and clinical trials to come, Antonson says the results are more translatable to humans than previous mouse studies because of the viral exposure they chose.
"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," she said. "In pregnant people, getting a flu shot can reduce severe outcomes, so please get vaccinated."
The study, "Influenza A virus infection during pregnancy increases transfer of maternal bloodborne molecules to fetal tissues," is published in Brain Behavior and Immunity [DOI: 10.1016/j.bbi.2025.106069 ].
Research in the College of ACES is made possible in part by Hatch funding from USDA's National Institute of Food and Agriculture. This study was also supported by the Roy J. Carver Charitable Trust (grant #23- 5683) and a Department of Animal Sciences Matchstick Grant.
Antonson is also affiliated with the Beckman Institute and the Interdisciplinary Health Sciences Institute at U. of I.
