Moderately pathogenic maternal influenza A virus infection disrupts placental integrity but spares the fetal brain

Maternal infection during pregnancy is a known risk factor for offspring mental health disorders. Animal models of maternal immune activation (MIA) have implicated specific cellular and molecular etiologies of psychiatric illness, but most rely on pathogen mimetics. Here, we developed a mouse model of live H3N2 influenza A virus (IAV) infection during pregnancy that induces a robust inflammatory response but is sublethal to both dams and offspring. We observed lung inflammatory cytokine production and severely diminished weight gain in IAV-infected dams. This was accompanied by immune cell infiltration in the placenta and partial breakdown of placental integrity. However, indications of IL-17A signaling and fetal neuroinflammation, which are hallmarks of mimetic-induced MIA, were not detected. Our results suggest that mild or moderately pathogenic IAV infection during pregnancy does not inflame the developing fetal brain, and highlight the importance of live pathogen infection models for the study of MIA. Highlights A mouse model of influenza A virus (IAV) infection during pregnancy was established Moderate IAV infection induced lung inflammation and blunted weight gain in dams Maternal IAV infection caused mild pathology in the placenta without pup loss Moderate gestational IAV infection did not induce fetal brain inflammation An IAV infection severity threshold may exist for inducing fetal neuroinflammation