Asthma is the most common disease of childhood in the United States. The role of microbial flora and allergens in asthma development is poorly understood. We found reduced pro-inflammatory Th2 cytokine production at age 2, reduced risk of eczema, and subsequent reduced allergy/allergic rhinitis risk by age 7 in children with elevated levels in infancy of home endotoxin, the biologically active form of lipopolysaccharide (LPS) contained in the outer membrane of gram-negative bacteria. In contrast, elevated early- life levels of dust mite increased allergic sensitization and active asthma risk;elevated home fungal levels in infancy increased allergic rhinitis risk. Endotoxin was correlated with other microbial flora (e.g., muramic acid, a marker for gram + bacteria, fungi);it may be a marker for an array of exposures recognized by antigen presenting cells (APCs) as pathogen-associated-molecular patterns (PAMPS). Ligation of PAMPS to innate APCs or regulatory cells may result in downregulation of allergic adaptive immune responses, or may result in airway inflammation depending on dose, timing and genes. In preliminary analyses, elevated muramic acid and elevated endotoxin were both linked to asthma symptom protection at age 7, though paradoxically, endotoxin predicted increased infant wheeze. We propose to extend our prospective longitudinal study of children of asthmatic/allergic parents to examine multiple microbial PAMP influences on asthma and immune development, following our birth cohort through the early teen years, a period of significant transition for allergy and asthma. We hypothesize that by the early teen years: (1) Early life exposure to home endotoxin will be associated with protection against allergic rhinitis and allergic sensitization. The relationship of endotoxin to wheeze, asthma and the secondary phenotypes of airway obstruction and airway inflammation, will be dependent on dose, timing, persistence of exposure, and host factors. As a marker for multiple PAMPS, endotoxin will be correlated with muramic acid, which will have similar effects on allergic rhinitis, wheeze, asthma and allergic sensitization. (2) Early life exposure to home fungi will be a risk factor for allergic rhinitis, wheeze, asthma and allergic sensitization. Fungal irritant and allergenic effects will dominate over the potential protective effects of fungi as PAMPS. (3) Reduction in bacterial PAMP exposures will be linked to reduced innate (TLR2, TLR4, MyD88, sCD14, IL-12) and regulatory (foxp3, IL-10, TGF-?) gene expression and cytokine production, which in turn will lead to reduced adaptive Th1 (IFN-?) cytokine production, elevated pro-allergic Th2 (IL-4, IL-13) cytokine production and subsequent allergic sensitization. Understanding the evolution of the allergic immune response to microbial flora and correlated cofactors is an important key to developing better environmental or pharmacologic controls to either prevent or switch off the tendency to allergy and asthma in childhood.

Public Health Relevance

(unchanged) The potential benefit to society is great, if this study contributes to an understanding of mechanisms for development of allergy and asthma in childhood, and to environmental factors that influence these mechanisms. Approximately 40 percent of families in the U.S. will have a history of asthma or allergies in one of the parents;the study will be of particular benefit to these families.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI035786-16
Application #
7650894
Study Section
Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
Program Officer
Plaut, Marshall
Project Start
1994-06-01
Project End
2011-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
16
Fiscal Year
2009
Total Cost
$895,189
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Bunyavanich, Supinda; Rifas-Shiman, Sheryl L; Platts-Mills, Thomas A et al. (2016) Prenatal, perinatal, and childhood vitamin D exposure and their association with childhood allergic rhinitis and allergic sensitization. J Allergy Clin Immunol 137:1063-1070.e2
Hanson, Blake; Zhou, Yanjiao; Bautista, Eddy J et al. (2016) Characterization of the bacterial and fungal microbiome in indoor dust and outdoor air samples: a pilot study. Environ Sci Process Impacts 18:713-24
Tse, Sze Man; Coull, Brent A; Sordillo, Joanne E et al. (2015) Gender- and age-specific risk factors for wheeze from birth through adolescence. Pediatr Pulmonol 50:955-62
Behbod, B; Sordillo, J E; Hoffman, E B et al. (2015) Asthma and allergy development: contrasting influences of yeasts and other fungal exposures. Clin Exp Allergy 45:154-63
Sordillo, Joanne E; Kelly, Roxanne; Bunyavanich, Supinda et al. (2015) Genome-wide expression profiles identify potential targets for gene-environment interactions in asthma severity. J Allergy Clin Immunol 136:885-92.e2
Bunyavanich, Supinda; Rifas-Shiman, Sheryl L; Platts-Mills, Thomas A et al. (2014) Peanut, milk, and wheat intake during pregnancy is associated with reduced allergy and asthma in children. J Allergy Clin Immunol 133:1373-82
Bunyavanich, Supinda; Rifas-Shiman, Sheryl L; Platts-Mills, Thomas A E et al. (2014) Peanut allergy prevalence among school-age children in a US cohort not selected for any disease. J Allergy Clin Immunol 134:753-5
Behbod, B; Sordillo, J E; Hoffman, E B et al. (2013) Wheeze in infancy: protection associated with yeasts in house dust contrasts with increased risk associated with yeasts in indoor air and other fungal taxa. Allergy 68:1410-8
Cook, Andrea J; Gold, Diane R; Li, Yi (2013) Spatial Cluster Detection for Longitudinal Outcomes using Administrative Regions. Commun Stat Theory Methods 42:2105-2117
Tse, Sze Man; Gold, Diane R; Sordillo, Joanne E et al. (2013) Diagnostic accuracy of the bronchodilator response in children. J Allergy Clin Immunol 132:554-559.e5

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