According to the World Health Organization, pneumonia is the leading cause of death in children worldwide, killing an estimated 1.4 million children annually – more than AIDS, malaria and tuberculosis combined. The neonatal lung environment is highly susceptible to pneumonia during respiratory infections. My graduate research lab has developed a neonatal model to influenza virus and in this model the immune cells consolidate in the lung interstitium rather than entering the airway . This study mimics autopsy sections taken from children who died from respiratory syncytial and influenza A viral infections . By utilizing human bronchial epithelial cells in an in vitro air-liquid interface culture model to mimic the in vivo human bronchial epithelium of adult and neonatal lungs my lab can evaluate the disparities between adult and neonatal lung cells. Human airway epithelial cells in the air-liquid interface model form pseudostratified layers with tight junctions, cilia and mucin production . Recent studies suggest that human bronchial epithelial cells are multipotent progenitors capable of differentiating into multiple central and peripheral lung cell types . I propose that the capacity of epithelial cell differentiation is altered between the adult and neonatal lung environments; possibly due to alveolarization taking place until approximately eight years of age. Therefore, immunoregulatory cytokines such as TGFβ and Interleukin 10 are constitutively expressed (unpublished work and ); I believe that these cytokines alter the bronchial epithelium to be more permissible to influenza viral infections. This research project will be a novel way to compare the adult and neonatal lung, and will offer expansion into other airway diseases such as asthma, bacterial lung infections and respiratory viruses. My research students will be able to examine epithelial cell development and differentiation using fluorescent microscopy, altered cell signaling by real time PCR for signaling, single immune cell analysis with flow cytometry and secreted cytokine analysis by ELISA.
1. Lines, J.L., et al., The migration of T cells in response to influenza virus is altered in neonatal mice. J Immunol, 2010. 185(5): p. 2980-8.
2. Welliver, T.P., et al., Severe human lower respiratory tract illness caused by respiratory syncytial virus and influenza virus is characterized by the absence of pulmonary cytotoxic lymphocyte responses. J Infect Dis, 2007. 195(8): p. 1126-36.
3. Dvorak, A.e.a., Do Airway Epithelium Air-Liquid Cultures Represent the In Vivo Airway Epithelium Transcriptome. American Journal of Respiratory Cell and Molecular Biology, 2011. 44: p. 465-473.
4. Delgado, O., et al., Multipotent capacity of immortalized human bronchial epithelial cells. PLoS One, 2011.
5. Qureshi, M.H., A.G. Harmsen, and B.A. Garvy, IL-10 modulates host responses and lung damage induced by Pneumocystis carinii infection. J Immunol, 2003. 170(2): p. 1002-9.
J. Breslow-Deckman, C. M. M., S. Birket, S. Hoskins, T. N. Ho, B. A. Garvy, and D. J. Feola. 2013. Linezolid Decreases Susceptibility to Secondary Bacterial Pneumonia Post-Influenza Infection in Mice Through its Effects on Interferon-gamma. J Immunol.; 191(4); 1792-9.
Lines, J.L., Hoskins, S. N., and B. A. Garvy. 2010. The Migration of T cells in Response to Influenza Virus is Altered in Neonatal Mice. J Immunol 185: 2980-8.
Asher, W. B., Hoskins, S. N., Slasor, L. A., Morris, D. H., Cook, E. M., D. L. Bautista. 2007. Two Model System of the α1A-Adrenoceptor Docked with Selected Ligands. J. Chem. Inf. Modeling.; 47(5); 1906-1912
Publications (in preparation)
Hoskins, S. N., Hollifield, M.L. and B. A. Garvy. Working title: T regulatory cells restrain T helper 2 cells to allow an effective neonatal immune response to Influenza A virus.
Lines, J.L., Hoskins, S. N., and B. A. Garvy. Working title: The immunodominance hierarchy of the T cell response to influenza virus is altered in neonatal mice.
Lines, J.L., Hoskins, S. N., and B. A. Garvy. Working title: The T cell response to influenza virus infection of neonatal mice is hindered by a reduction in lung dendritic cells.