Microbiome-induced changes following influenza infection during pregnancy - Project Summary Influenza A virus (IAV) impacts pregnant individuals and their offspring to a greater extent than the general population during pandemics and seasonal epidemics. Pregnancy is a risk factor for severe outcomes from IAV infection, including increased risk of hospital admission and death, and is also associated with adverse perinatal and fetal outcomes. While IAV does not replicate in the placenta, IAV infection induces placental damage and inflammation, which can be mitigated using steroids and result in reversed perinatal outcomes in a mouse model. The maternal gut microbiome is crucial in maintaining physiological homeostasis during pregnancy, but how virus-induced dysbiosis contributes to adverse fetal outcomes is unknown. I hypothesize that adverse fetal outcomes, including intrauterine growth restriction, may be enhanced by IAV- induced changes in the diversity and composition of the maternal gut microbiome. The goal of this project is to investigate the mechanisms by which the maternal gut microbiome contributes to adverse fetal and perinatal outcomes using an outbred pregnant mouse model of IAV infection. My preliminary data show that IAV infection reduces maternal fecal microbial diversity and bacteria associated with short-chain fatty acid (SCFA) production, which is associated with intrauterine growth restriction and developmental delays in offspring. The central hypothesis of this proposal is that placental damage, inflammation, and intrauterine growth restriction during IAV infection of pregnant dams are caused by changes in the maternal gut microbiome, which increases intestinal barrier permeability, reduces the production of microbial metabolites (SCFA), and enhances intestinal inflammatory immune cell populations. Utilizing my previous experience in clinical bacteriology and recently developed expertise with mouse models of pregnancy, Aim 1 will focus on characterizing changes in intestinal morphology, microbial metabolites, and intestinal immune cell populations after IAV infection. Aim 2 will investigate the direct effect of IAV-induced maternal gut dysbiosis on adverse perinatal outcomes using fecal-microbial transplantation. If changes in the maternal gut microbiome contribute to adverse fetal outcomes after IAV infection, then probiotic supplementation will reduce placental damage, inflammation, and intrauterine growth restriction. The research aims outlined in the proposal will assist in continuing my training in animal models, viral immunology, and microbiome-based experimental manipulations, further enhancing my expertise in the relationships between viral pathogens and native host bacteria.
