The heterogeneity of clinical manifestations to viral infections is vast, but fundamentally, little is known regarding the scientific basis for such discrepant responses. Recent paradigm-shifting work has shown the importance of the microbiota and its metabolites in host immunity and disease pathogenesis. It is paramount to understand the cellular and molecular mechanisms by which microbial metabolites are powerful modulators of host immunity and disease outcomes. This research directly relates to the objectives of the Children’s Discovery Institute as it seeks to improve childhood health. The proposed studies will use mouse models to understand and optimize translatable strategies for immune responses to infections, a major cause of pediatric morbidity and mortality.
· Define the relevant cell type(s) and mechanistic basis by which the microbiota augments interferon signaling and confers protection from influenza infection.
· Test the hypothesis that microbial metabolites drive maturation of the immune system.
· Test the hypothesis that immaturity of the microbiota and absence of microbial metabolites represent the mechanistic basis by which the young display heightened susceptibility to infection and inflammation.
These studies will elucidate how microbial metabolites impact host immunity and advance our understanding of childhood health and disease. This knowledge will be directly translatable and lead to important preventative and therapeutic interventions.