Summary: A new University of Illinois study finds that severe influenza A infection during pregnancy in mice disrupts both the placenta and fetal blood-brain barriers, permitting large blood-borne molecules — including fibrinogen — to enter the developing fetal brain. Those molecules concentrated in critical regions such as the subventricular zone and choroid plexus, raising concerns about potential effects on neural stem cells and long-term neurodevelopment.
The researchers stress that not every maternal infection causes damage; severity matters. Their results reinforce the value of preventing severe flu in pregnancy, for example through vaccination, to reduce risks to fetal brain health.
Key Facts
- Barrier breakdown: Severe influenza A caused the placenta and fetal blood-brain barrier to become permeable to large molecules.
- Fibrinogen transfer: The bloodborne inflammatory protein fibrinogen was detected in fetal brains following severe maternal infection.
- Severity threshold: Only the most severe infections produced leakage, consistent with human epidemiological patterns linking severe maternal illness to higher risk.
Source: University of Illinois
Overview
Researchers at the University of Illinois Urbana-Champaign report that live influenza A virus infection in pregnant mice can compromise selective barriers at the maternal-fetal interface and in the fetal brain. This is the first demonstration that a live seasonal flu infection produces measurable loss of placental and fetal blood-brain barrier integrity, allowing high–molecular-weight blood components to enter fetal tissue.
The study modeled moderate and severe clinical presentations of seasonal influenza by infecting pregnant mice with different doses of live virus. At a gestational stage comparable to the end of the human first trimester, investigators injected fluorescent tracers of varying molecular sizes into the maternal circulation to map transfer into fetal tissues. These tracers mimic different sizes of abundant blood proteins and reveal which molecules can cross into fetal organs.
When mothers experienced severe infection, the largest tracers — which should not cross an intact blood-brain barrier — accumulated in fetal brains. Tracers of multiple sizes also accumulated in placenta and fetal liver under severe infection conditions. The results indicate a dose-dependent effect: higher maternal viral burden produced greater transplacental and neurovascular leakage.
Importantly, the team also examined fibrinogen, a multifunctional blood protein associated with coagulation and known to exacerbate neuroinflammation in adult neurodegenerative conditions. For the first time in this prenatal context, fibrinogen was detected inside fetal brains following severe maternal influenza A infection.
Both fibrinogen and high–molecular-weight tracers concentrated in the subventricular zone (SVZ) and the choroid plexus (ChP) of fetal brains. These regions are crucial: the SVZ contains neural stem and progenitor cells that differentiate into radial glia and neurons, and the ChP produces cerebrospinal fluid and helps maintain CNS barrier function. Exposure of these sites to bloodborne inflammatory molecules could alter developmental trajectories.
The researchers note that fibrinogen in the brain can promote oxidative stress and reactive oxygen species production, processes that damage developing neurons and increase cell death. In adult models and human disease, fibrinogen accumulation correlates with neuroinflammation; this study raises the possibility that similar pathological interactions could begin prenatally under severe maternal infection.
While these findings derive from a mouse model and further preclinical and clinical work is needed, the use of live influenza virus and clinically relevant dosing makes the results more translatable than some prior studies that used inactivated pathogens or synthetic immune mimics. The dose-dependent pattern supports the concept of an infection-severity threshold: mild or moderate maternal illness may not breach barriers, whereas severe disease can permit transfer of harmful molecules into the fetal compartment.
Given this threshold effect, the investigators emphasize preventive measures that reduce severity of maternal influenza — including vaccination — as a practical approach to lower the chance of fetal brain exposure to bloodborne inflammatory agents.
Funding: Research in the College of Agricultural, Consumer and Environmental Sciences (ACES) received support from USDA National Institute of Food and Agriculture Hatch funding, the Roy J. Carver Charitable Trust (grant #23-5683), and a Department of Animal Sciences Matchstick Grant.
Lead investigators are affiliated with the Department of Animal Sciences, the Neuroscience Program, the Beckman Institute, and the Interdisciplinary Health Sciences Institute at the University of Illinois.
About this neurodevelopment research news
Author: Lauren Quinn
Source: University of Illinois
Contact: Lauren Quinn – University of Illinois
Image: Image credit: Neuroscience News
Original Research: Open access. “Influenza A virus infection during pregnancy increases transfer of maternal bloodborne molecules to fetal tissues” by Adrienne Antonson et al., published in Brain, Behavior, and Immunity.
Abstract
Influenza A virus infection during pregnancy increases transfer of maternal bloodborne molecules to fetal tissues
Maternal influenza A virus (IAV) infection is epidemiologically associated with increased risk for neurodevelopmental disorders in offspring. The underlying pathophysiological mechanisms remain under investigation. We hypothesize that maternal immune activation provoked by IAV disrupts selective permeability at the maternal-fetal interface, increasing the transfer of blood-derived molecules into the fetal compartment and potentially initiating inflammatory cascades implicated in neurodevelopmental disorder etiology.
Using a murine model of seasonal IAV infection during pregnancy, we examined placental and fetal brain barrier properties after maternal challenge. We observed enhanced transplacental transfer of fluorescently labeled tracers from maternal circulation to key neurodevelopmental regions, including the subventricular zone and choroid plexus of fetal brains. These effects were most pronounced following the highest maternal IAV dose. A parallel pattern occurred for accumulation of bloodborne fibrinogen in the same brain regions, with levels increasing alongside maternal infection severity. Fibrinogen accumulation correlated with increased Iba1+ immunofluorescence, suggesting interaction with microglia-like cells. Collectively, the data indicate that IAV-induced maternal immune activation enhances transfer of blood-derived molecules into fetal tissues and may activate proinflammatory pathways in Iba1+ cells, with potential implications for neurodevelopment.