Environmental modulation of mucosal immunity: Opportunities in respiratory viral infections

Abstract

The exact cause of severe disease in children during primary RSV infections is not completely clear. There is a link with viral load, but differences virus strains do not seem to be the major reason why in some children the disease manifests as a mild cold while others suffer from a severe lower respiratory tract disease. The prevalence of severe lower respiratory tract infection due to RSV is high in the neonatal period. The immune response in this age group is characterized by suppressed innate immune responses and a Th2 bias, reasons for poorly effective immune responses to infection and vaccination. During the neonatal period maternally derived antibodies and maturation of neonatal immunity via microbial colonization of mucosal surfaces are both important factors to protect the newborn against pathogens upon the first encounter. However, the presentation of antibody opsonized virus to various cell types alters the innate pathogen recognition pathways, affecting the onset of subsequent immune responses evoked by these cells and subsequently the ability to respond to RSV infections. Furthermore, altered mucosal colonization due to antibiotic treatment, environmental challenges or pharmaceutical components might affect the development of neonatal immunity. In this thesis we investigate the possible influence of (maternally derived) RSV specific antibodies and microbiome manipulation via specific prebiotic oligosaccharides and broad spectrum antibiotics on immunity against RSV. We show in our studies that the use of highly neutralising antibodies or antibiotics in new-borns should carefully be evaluated for their potential to alter innate immune responses and the development of adaptive immunity to RSV and certainly also other pathogens. Extrapolation from our mouse model suggests that antibiotics used in the neonatal period might increase the risk of developing severe RSV bronchiolitis and susceptibility to develop allergic disease in later life. A better understanding of the mechanism by which vaccine induced immune responses can be amplified or altered by microbiome manipulation, might in the future lead to promising options whereby dietary manipulation support neonatal immune development and vaccine efficacy.