The developing immune response in infants is central to establishing a balanced system that reacts appropriately to infectious stimuli but does not induce altered disease states with potential long term sequelae. Respiratory syncytial virus (RSV) is often the first clinically relevant pathogen encountered in life and has been suggested to alter the immune system, affecting future responses, such as those leading to childhood allergies and asthma. Other early life processes also contribute to the development of immune responses including assembly of the microbiome, which appears to have a particularly important role early in life and significantly altered after RSV infection in our studies. Our preliminary data show that early neonatal infection with RSV alters bone marrow-derived dendritic cells (DC) at 4 weeks of age suggesting an prolonged altered innate immune phenotype due to the early RSV infection. When neonatal RSV infected mice are sensitized to allergens at 4 weeks of age, mice show an exacerbated allergic disease phenotype compared to those that were not infected. These latter data reflect clinical findings where neonates have increased risk of severe RSV infection and those most severely infected have an increased incidence to develop allergic disease during childhood. Our preliminary data also highlight that the change in DC function is associated with major shifts in the neonatal RSV-induced bacterial community composition of the gut and changes in plasma metabolite profiles, most notably xanthine/uric acid metabolites. In the present proposal our hypothesis is that neonatal RSV infection alters the local and systemic immune responses through alteration of the microbiome that is coincident with changes in systemic metabolite production profiles that promote altered programming of DC leading to increased susceptibility for the development of allergic disease. We have provided strong preliminary data that demonstrate that early life RSV infection of the lungs alters the development of the systemic immune responses in neonates, leads to gut microbiome alteration, and changes the systemic metabolic profile of the neonate. In particular, our data suggest that the xanthine/uric acid metabolic pathway that feeds into inflammasome activation is highly upregulated and is associated with the altered microbiome during RSV infection. As uric acid promotes inflammasome activation and upregulation of IL-1? and other inflammatory mediators we propose that this pathway will significantly contribute to the long- term effects on the immune system. These early events modify impact the progression of allergic responses systemically later in life through the long-term alteration of immune cell phenotypes. The investigation of the mechanisms that govern these responses will establish new paradigms to be tested in patient populations and represent a significant gap in our understanding of how infectious organisms alter the developing neonatal immune system.
The investigation of the mechanisms that govern neonatal immune responses being explored in this proposal will establish new paradigms to be tested in patient populations and represent a significant gap in our understanding of the developing neonatal immune system. The impact of neonatal respiratory syncytial virus infections on the development of the microbiome and changes in metabolites that influence allergic disease will be also examined to identify novel pathways of disease development.
