: Respiratory syncytial virus (RSV) infection is the most common cause of respiratory disease leading to hospitalization in children. Preterm infants are especially susceptible to severe RSV infection. Respiratory epithelium is an initial site of RSV infection and epithelial cells along with alveolar macrophages (AM) and dendritic cells (DC) are vital to innate and adaptive immune responses. However, the extent of innate immune gene expression by epithelia and AM-DC in preterm infants can be variable/limited. The hypothesis is that: Reduced innate immunity by respiratory epithelia and AM-DC preterm enhances susceptibility to RSV infection This hypothesis is based on the facts above and our preliminary data in lambs demonstrating limited expression of surfactant proteins A and D (SP-AD), sheep beta-defensin-1 (SBD-1), and Toll-like receptor 4 (TLR4) preterm. It will be tested in preterm lambs which have close similarities with human disease including susceptibility, lesions, and innate immunity.
Specific Aim 1 compares expression of key innate immune genes (SBD-1, SP-AD, TLR4) and protein/peptide production in vivo as well as AM-DC cytokine expression in pre- and full-term lung. It also tests the hypothesis that limited epithelial cell proliferation and/or differentiation pre-term underlie(s) the mechanistic basis for limited SP-AD, SDB-1 expression and tests this by comparing transcriptional activity, protein/peptide production in pre- and full term cultured cells with or without cell proliferation and differentiation.
Specific Aim 2 tests the hypothesis that SP-AD, SBD-1 and AM-DC responses to RSV are less at pre- than full-term in the lamb model and in vitro with cultured epithelial cells. A second hypothesis, that increased cell proliferation and/or differentiation of epithelia protects against RSV infection, will be tested in vitro with treatments from Aim 1. The extent to which SP-AD, SBD-1 directly prevent RSV infection will be tested with RNAi assays.
Specific Aim 3 tests the hypothesis that yet other innate immune genes expressed with cell proliferation/differentiation prevent RSV infection.
This Aim uses gene expression profiling of primary polarized human lung cells and a respiratory epithelia-specific probe set (Unigene) that is the most well-annotated and defined gene target set to date. It also identifies ovine orthologs of human genes and test for impaired/reduced expression preterm. This team combines veterinary and human medical expertise to attain the goal of this project: to discover the reason(s) for inadequate expression of SP-AD, SBD-1 and other innate immune genes as well as AMDC responses at preterm that predispose to RSV infection. The work is significant because it discovers the underlying basis for RSV susceptibility preterm and mechanistic approaches to enhance innate immunity. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI062787-02
Application #
7113126
Study Section
Special Emphasis Panel (ZRG1-IMM-F (03))
Program Officer
Cho, David
Project Start
2005-08-15
Project End
2010-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
2
Fiscal Year
2006
Total Cost
$380,843
Indirect Cost
Name
Iowa State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
005309844
City
Ames
State
IA
Country
United States
Zip Code
50011
Derscheid, R J; Ackermann, M R (2013) The innate immune system of the perinatal lung and responses to respiratory syncytial virus infection. Vet Pathol 50:827-41
Sow, Fatoumata B; Gallup, Jack M; Derscheid, Rachel et al. (2012) Ontogeny of the immune response in the ovine lung. Immunol Invest 41:304-16
Derscheid, Rachel J; Ackermann, Mark R (2012) Perinatal lamb model of respiratory syncytial virus (RSV) infection. Viruses 4:2359-78
Olivier, Alicia K; Gallup, Jack M; van Geelen, Albert et al. (2011) Exogenous administration of vascular endothelial growth factor prior to human respiratory syncytial virus a2 infection reduces pulmonary pathology in neonatal lambs and alters epithelial innate immune responses. Exp Lung Res 37:131-43
Lazic, Tatjana; Sow, Fatoumata B; Van Geelen, Albert et al. (2011) Exposure to ethanol during the last trimester of pregnancy alters the maturation and immunity of the fetal lung. Alcohol 45:673-80
Fach, Sasha J; Olivier, Alicia; Gallup, Jack M et al. (2010) Differential expression of cytokine transcripts in neonatal and adult ovine alveolar macrophages in response to respiratory syncytial virus or toll-like receptor ligation. Vet Immunol Immunopathol 136:55-64
Ackermann, Mark R; Derscheid, Rachel; Roth, James A (2010) Innate immunology of bovine respiratory disease. Vet Clin North Am Food Anim Pract 26:215-28
Radi, Zaher A; Meyerholz, David K; Ackermann, Mark R (2010) Pulmonary cyclooxygenase-1 (COX-1) and COX-2 cellular expression and distribution after respiratory syncytial virus and parainfluenza virus infection. Viral Immunol 23:43-8
Lazic, Tatjana; Matic, Milan; Gallup, Jack M et al. (2010) Effects of nicotine on pulmonary surfactant proteins A and D in ovine lung epithelia. Pediatr Pulmonol 45:255-62
Gallup, J M; Sow, F B; Van Geelen, A et al. (2010) SPUD qPCR assay confirms PREXCEL-Q softwares ability to avoid qPCR inhibition. Curr Issues Mol Biol 12:129-34

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