Influenza A virus during pregnancy disrupts maternal intestinal immunity and fetal cortical development in a dose- and time-dependent manner

Epidemiological studies link neurodevelopmental disorders (NDDs) with exposure to maternal viral infection in utero. It is hypothesized that the mechanism governing this link involves the activation of maternal intestinal T helper 17 (T H 17) cells, which produce effector cytokine interleukin (IL)-17. While IL-17 is implicated as a major driver of fetal brain abnormalities, this inflammation-induced T H 17 pathway has not been thoroughly examined in models of live viral infection during pregnancy. Influenza A virus (IAV) infection is consistently linked to offspring NDDs and can result in host intestinal dysregulation. Therefore, it is possible that intestinal T H 17 cells and subsequent production of IL-17 could drive fetal brain abnormalities during gestational IAV infection. To test this, we inoculated pregnant mice with two infectious doses of IAV and evaluated peak innate and adaptive immune responses in the dam and fetus. While respiratory IAV infection led to dose-dependent maternal colonic shortening and microbial dysregulation, there was no elevation in intestinal T H 17 cells nor IL-17. Fetal cortical abnormalities and global changes in fetal brain transcripts were observable in the high-dose IAV group, despite a lack of IL-17 signaling. Profiling fetal microglia and border-associated macrophages (BAMs) –potential cellular mediators of IAV-induced cortical abnormalities –revealed dose-dependent differences in the numbers of BAMs but not microglia. Overall, our data support the idea of an infection severity threshold for downstream maternal inflammation and fetal cortical abnormalities, confirming the use of live pathogens in NDD modeling to better evaluate the complete immune response and to improve translation to the clinic.