Neonatal Respiratory Virus Infection Shapes Pulmonary Function in Adult Mice

Abstract

Respiratory syncytial virus (RSV) and influenza are the two most common causes of acute lower respiratory tract infections in infants. Epidemiological data suggest that both severe RSV and influenza infections during infancy are associated with long-term pulmonary function abnormalities. Despite of the severe burdens of RSV and influenza infections in infants, no efficacious vaccines are available for RSV and the current vaccine strategy for influenza is inconvenient due to the fact that vaccines are made annually based on the prediction of circulating strains in the next season. New strategies in vaccine development have been slow to arrive partly due to the fact that pathogenesis of RSV and influenza, especially in infants, is not well understood; and this is further complicated by the fact that most researchers use adult animal models to study immunopathology observed in human infants. To better model the infections of these two viruses in infants, we established neonatal mouse models for RSV and influenza infections. In our neonatal mouse model, both RSV and influenza infections led to long-term airway hyperreactivity associated with persistent pulmonary inflammation. An inchoate CD8+ T cell response was found to play a significant role in the pathogenesis of neonatal influenza infection; while a Th2 (IL-4-producing CD4+ T helper cell)-biased immune response was responsible for the pathogenesis of neonatal RSV infection and led to Th2-skewed secondary responses in adult mice originally infected as neonates. In an effort to seek a better vaccine strategy for RSV infection, we used antisense oligonucleotides (ASO) against IL-4 receptor alpha (IL-4Ralpha) to modulate the T cell responses at the time of primary RSV infection. Upon reinfection with RSV, IL-4Ralpha ASO treated mice were completely protected from airway hyperreactivity. This finding suggested that there was a delicate balance between Th1 (IFN-gamma-producing CD4+ T helper cell) and Th2 cell responses and that only a slight push in one direction (i.e., Th1) had a tremendous impact on subsequent diseases. Our data indicate that modulation of the immune responses to RSV during infantile infection may be of significant benefit to infants and that IL-4Ralpha may be part of a viable vaccine strategy.