The Iong-term objective of this proposal is to test a modified version of the hygiene hypothesis, in which genetic variants of TLRs in human hosts interact with different microbial colonizers to wield a positive or negative influence on the development of asthma. This hypothesis is proposed as a new and more intricate paradigm for gene by environment interactions as determinants of susceptibility to asthma and asthma-associated allergies. The following specific aims are proposed: 1) To determine the relation of TLR2 genotypes,TLR2 protein expression and S. aureus colonization pattern to risk for the development of atopic dermatitis in children; 2) To determine the variation in airway epithelial cell activation invoked by S. aureus-derived ligands and to link the variation to TLR2 genotype, expression and/or colonization pattern; 3) To establish the influence of TLR5 SNPs on TLR5 expression in innate immune cells among children with different H pylori colonization patterns; and 4) To determine the relation of patterns of S aureus and H pylori colonization to asthma development and sensitization to asthma-related aeroallergens by age 6. Data will be obtained from nasal swabs, peripheral blood cells, exhaled breath condensates, cultured airway epithelial cell lines, and primary bronchial cells. By completing these four aims, clarification will be provided as to 1) whether S aureus colonization provides an explanation for the link between atopic dermatitis and the development of asthma and is a direct causative factor in the development of asthma; 2) whether S. aureus colonization interacts with TLR2 SNP to predispose to the AD/asthma pathway; and 3) whether H pylori colonization inhibits the development of asthma by age 6 via interaction with a TLR5 stop codon SNP and/or other SNPs. If correct, the hypothesis offers an explanation for the oft-noted differences in the relation of human gene variants to asthma prevalence in different regions of the world and for the increase in asthma affecting a large portion of the world.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI061811-05
Application #
7384413
Study Section
Special Emphasis Panel (ZAI1-KLW-I (M6))
Program Officer
Minnicozzi, Michael
Project Start
2004-09-01
Project End
2010-02-28
Budget Start
2008-03-01
Budget End
2010-02-28
Support Year
5
Fiscal Year
2008
Total Cost
$548,225
Indirect Cost
Name
University of Arizona
Department
Pharmacology
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Rothers, Janet; Stern, Debra A; Lohman, I Carla et al. (2018) Maternal Cytokine Profiles during Pregnancy Predict Asthma in Children of Mothers without Asthma. Am J Respir Cell Mol Biol 59:592-600
Sevgican, Ufuk; Rothers, Janet; Stern, Debra A et al. (2012) Predictors of neonatal production of IFN-? and relation to later wheeze. J Allergy Clin Immunol 129:567-8, 568.e1
Rothers, Janet; Halonen, Marilyn; Stern, Debra A et al. (2011) Adaptive cytokine production in early life differentially predicts total IgE levels and asthma through age 5 years. J Allergy Clin Immunol 128:397-402.e2
Rothers, Janet; Wright, Anne L; Stern, Debra A et al. (2011) Cord blood 25-hydroxyvitamin D levels are associated with aeroallergen sensitization in children from Tucson, Arizona. J Allergy Clin Immunol 128:1093-9.e1-5
Custovic, Adnan; Rothers, Janet; Stern, Debbie et al. (2011) Effect of day care attendance on sensitization and atopic wheezing differs by Toll-like receptor 2 genotype in 2 population-based birth cohort studies. J Allergy Clin Immunol 127:390-397.e1-9
Maier, Raina M; Palmer, Michael W; Andersen, Gary L et al. (2010) Environmental determinants of and impact on childhood asthma by the bacterial community in household dust. Appl Environ Microbiol 76:2663-7
Su, Y; Rothers, J; Stern, D A et al. (2010) Relation of early antibiotic use to childhood asthma: confounding by indication? Clin Exp Allergy 40:1222-9
Halonen, Marilyn; Lohman, I Carla; Stern, Debra A et al. (2009) Th1/Th2 patterns and balance in cytokine production in the parents and infants of a large birth cohort. J Immunol 182:3285-93
Olsen, Colin E; Liguori, Andrew E; Zong, Yue et al. (2008) Arsenic upregulates MMP-9 and inhibits wound repair in human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol 295:L293-302
Rothers, Janet; Stern, Debra A; Spangenberg, Amber et al. (2007) Influence of early day-care exposure on total IgE levels through age 3 years. J Allergy Clin Immunol 120:1201-7

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