ARRA: Host defense against influenza virus in the lungs of neonatal mice

Infants are particularly susceptible to respiratory infections which have been attributed to an immature and naïve immune system that is characterized by suboptimal antigen presentation and a I helper cell bias toward Th2-type cytokines. However, little is known about how the post-natally developing lungs contribute to susceptibility to pulmonary infection. Immune homeostasis in the lungs is controlled by a number of factors including epithelial cell production of IL-lO and TGF~ and expression of CD200/CD200R on epithelial cells and alveolar macrophages, respectively. Our data shows elevated levels of TG93 in the lungs of infant mice over the first 3 weeks of life. Moreover, we have previously reported that IL-I 0 mRNA is constitutively expressed in neonatal lungs. We speculate that these anti-inflammatory cytokines increase the threshold of activation of immune cells in the lungs resulting dampening of inflammation in neonatal lungs. We found that unlike adults, neonatal mice develop interstitial pneumonia in response to influenza virus infection which corresponds to differential expression of chemokines compared to adult mice. The goal of this project is to determine mechanisms that contribute to the differences in I cell migration that may result in the greater susceptibility to virus in neonatal mice. We will address the following hypothesis: The neonatal lung environment alters T cell responses to infection leading to interstitial pneumonia and a worse outcome than in adults. Two aims are proposed: 1) To determine whether neonatal T cells and/or the neonatal lung environment are responsible for development of interstitial pneumonia in response to influenza virus; and 2) To determine the mechanisms responsible for the migration of T cells into the neonatal interstitial spaces but not alveolar spaces. We have chosen to use influenza virus as a models system since influenza virus infection causes more morbidity and mortality than any other infection preventable by vaccination and hospitalization rates among infants with influenza virus rival those of the elderly. Understanding the underlying mucosal immune response to influenza virus in infants is an important step in formulating new treatment strategies for infants.