Maternal vaccination partially protects piglets against influenza A virus associated alteration of the microbiome and hippocampal gene expression

Influenza A virus (IAV) causes respiratory disease with systemic complications in a variety of avian and mammalian hosts, including humans and pigs. Infection with IAV in newborns can be particularly damaging as viral infection is known to disrupt the rapid developmental processes that occur during this period. Maternal IAV vaccination can reduce the risk of IAV infection in infants, but it is unknown whether passive transfer of anti-IAV antibodies protect against the downstream complications of infection. In this study, we evaluated the impact of maternal vaccination on the gut and nasal microbiota development and hippocampal transcriptome in neonatal piglets infected with influenza A virus. Sows were either vaccinated with an experimental influenza A vaccine at 70- and 90-days gestation, or mock-vaccinated with PBS. Neonatal piglets born from vaccinated and unvaccinated sows were challenged with a pathogenic IAV isolate or mock-challenged with PBS at 6 days post-farrowing and euthanized five days post challenge. Vaccination significantly reduced lung lesions and infectious viral load in piglets. Nasal and gut microbial community development was also partially protected from viral disruption as indicated by increased deviation from pre-challenge timepoints compared to animals challenged with the virus from unvaccinated mothers. Bulk RNA sequencing of hippocampal tissue identified 1146 differentially expressed genes (FDR < 0.05) between groups. IAV-infected piglets from vaccinated sows showed increases in genes related to viral immune responses, while IAV-infected piglets from unvaccinated sows showed increases in genes related to neurogenesis and decreases in genes related to vascular development. Many of these differentially regulated genes were strongly correlated with microbial community abundances, indicating that the microbiota may contribute to IAV outcomes. Notably, nasal microbial abundances intricately connected with hippocampal gene expression patterns, suggesting a strong nasal microbiome-brain communication axis in early development. Together, our results indicate that maternal vaccination partially protects neonatal piglets against influenza virus infection and mitigates the potential long-term impacts of IAV infection on the microbiome and cognition.