Fibrinogen as a Driver of Oxidative Stress and Apoptosis in the Fetal Brain After Maternal Influenza

Maternal infection during pregnancy has been associated with increased risk for adverse neurodevelopmental outcomes, yet the mechanisms linking maternal inflammation to fetal brain vulnerability remain under active investigation. Here, we used a mouse-adapted gestational influenza A virus (IAV; X31) model of maternal immune activation to assess cerebrovascular leakage of fibrinogen, fibrinogen-microglia colocalization, oxidative stress-related responses, and cell death in fetal brains. Maternal IAV infection induced classic sickness symptoms and fetoplacental growth restriction, reflected by reduced fetal weight, crown-to-rump length, and placental weight. In the fetal brain, maternal flu increased fibrinogen accumulation in the subventricular zone (SVZ), while fibrinogen-microglia colocalization increased in the SVZ, thalamus-third ventricle interface, and whole hemisphere, suggesting broad fibrinogen-microglia proximity. These changes were accompanied by increased Iba1⁺/p47 ^phox⁺ cell density in the same regions, consistent with greater microglial oxidative state. Because these regions contain neurogenic SOX2⁺ progenitors, we assessed whether fibrinogen accumulation and increased oxidation coincided with altered progenitor maintenance or survival. Although fetal SOX2⁺ neural progenitor density was not broadly altered by maternal flu, apoptosis analyses revealed a treatment- and sex-biased vulnerability, with males from IAV-infected dams demonstrating increased cell death, particularly within SOX2⁺ progenitors. Consistent with these in vivo findings, conditioned medium from fibrin-stimulated BV-2 microglia-like cells increased neural progenitor cell death in vitro , including amongst SOX2⁺ populations. Together, these findings support a framework in which maternal IAV-induced inflammation contributes to fibrinogen accumulation, microglial oxidative stress, and male-biased neural progenitor vulnerability in fetal brain regions critical for neurodevelopment.