Infants are particularly susceptible to respiratory infections which have been attributed to an immature and naive immune system that is characterized by suboptimal antigen presentation and a T 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-10 and TGFB and expression of CD200/CD200R on epithelial cells and alveolar macrophages, respectively. Our data shows elevated levels of TGFB in the lungs of infant mice over the first 3 weeks of life. Moreover, we have previously reported that IL-10 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 T 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. Infants that die from influenza virus have been shown to develop interstitial pneumonia with little infiltration of T cells into the alveolar space. The goal of this project is to understand the processes in post-natally developing lungs that leads to development of interstitial pneumonia in response to infection. Understanding the nature of the failure of the neonatal immune system to control influenza virus is important for generation of new vaccine and treatment strategies.

Public Health Relevance

Infants that die from influenza virus have been shown to develop interstitial pneumonia with little infiltration of T cells into the alveolar space. The goal of this project is to understand the processes in post-natally developing lungs that leads to development of interstitial pneumonia in response to infection. Understanding the nature of the failure of the neonatal immune system to control influenza virus is important for generation of new vaccine and treatment strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI083528-01
Application #
7706840
Study Section
Special Emphasis Panel (ZAI1-PTM-I (M2))
Program Officer
Rothermel, Annette L
Project Start
2009-08-15
Project End
2011-07-31
Budget Start
2009-08-15
Budget End
2010-07-31
Support Year
1
Fiscal Year
2009
Total Cost
$217,900
Indirect Cost
Name
University of Kentucky
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Oliphant, Samantha; Lines, J Louise; Hollifield, Melissa L et al. (2015) Regulatory T Cells Are Critical for Clearing Influenza A Virus in Neonatal Mice. Viral Immunol 28:580-9
Breslow-Deckman, Jessica M; Mattingly, Cynthia M; Birket, Susan E et al. (2013) Linezolid decreases susceptibility to secondary bacterial pneumonia postinfluenza infection in mice through its effects on IFN-?. J Immunol 191:1792-9
Lines, J Louise; Hoskins, Samantha; Hollifield, Melissa et al. (2010) The migration of T cells in response to influenza virus is altered in neonatal mice. J Immunol 185:2980-8