Asthma is a chronic inflammatory disease that profoundly impacts the quality of life of affected individuals and heavily burdens the national health care system. To reduce the prevalence of asthma, a greater understanding of the mechanisms by which environmental factors trigger pathological changes in the airway is needed. Exposure to common environmental allergens along with respiratory allergies to house dust mites, fungal spores, and cockroaches are risk factors in the development of asthma. Chitin is a common thread among these irritants, since it is present in the exoskeleton of arthropods, the shells of crustaceans, and the cell wall of fungi. Chitin, which is the second most abundant polymer on our planet, is a linear polymer of N- acetylglucosamine. In recent work, exposure of mice to chitin particles induced the accumulation of immune cells associated with allergy. Mammalian chitinases and chitinase-like proteins are elevated in individuals with asthma and have been implicated in allergic inflammation. These facts raise the possibility that environmental exposure to chitin is a key factor in the pathogenesis of asthma. However, the mechanism by which chitin is recognized by the innate immune system is not well established and further study of the role of chitin exposure in the pathogenesis of asthma is needed. The scientific goal of this proposal is to investigate the mechanisms of chitin recognition in the airway and to understand the role of chitin exposure in the development of asthma. To achieve this goal, we will create defined N-acetylglucosamine oligosaccharides to probe and determine the minimal chain length that is recognized by cells of the innate immune system such as macrophages and epithelial cells. We will also define the cellular components of the inflammatory response to chitin in the airway using mouse models of asthma and in vitro cell co-culture methods. Finally, we will examine how exposure to chitin influences the subsequent priming of allergen specific T-cells using allergen specific transgenic T-cells in a mouse model of asthma.
The specific aims are to: (1) define the oligosaccharide that mediates recognition of chitin and reproduces the inflammatory response to chitin, (2) elucidate the role of chitin-exposed epithelial cells alternatively activating alveolar macrophages and (3) identify the role of chitin exposure in polarizing allergen specific T-cell responses in a fungal model of asthma. From a training standpoint, this work will be pursued in an environment characterized by: 1) an vibrant, dynamic sponsor's laboratory, 2) a strong institutional training program in environmental toxicology, 3) a research setting that is among the strongest in the nation for studying the basic and clincal science of asthma, thereby fostering many opportunities for scientific interactions with other asthma investigators, and 4) a close alliance with the intellectual resources and research cores available for training through the American Asthma Foundation.
Asthma is a chronic disease that significantly reduces quality of life and places a large burden on the national health system. The scientific purpose of this proposal is to study the role of environmental exposure to chitin, which is found in the environment in insects, crustaceans, and mold spores, in the development of asthma. The results of these investigations will help to identify new therapeutic targets allowing clinical interventions early in the development of asthma.
|Roy, René M; Paes, Hugo C; Nanjappa, Som G et al. (2013) Complement component 3C3 and C3a receptor are required in chitin-dependent allergic sensitization to Aspergillus fumigatus but dispensable in chitin-induced innate allergic inflammation. MBio 4:|
|Roy, René M; Klein, Bruce S (2013) Fungal glycan interactions with epithelial cells in allergic airway disease. Curr Opin Microbiol 16:404-8|
|Roy, René M; Wüthrich, Marcel; Klein, Bruce S (2012) Chitin elicits CCL2 from airway epithelial cells and induces CCR2-dependent innate allergic inflammation in the lung. J Immunol 189:2545-52|
|Roy, René M; Klein, Bruce S (2012) Dendritic cells in antifungal immunity and vaccine design. Cell Host Microbe 11:436-46|