Mold Induced Asthma: Not all Molds are Created Equal

There is considerable evidence supporting that mold exposure is a major contributor to the development of asthma. The identification of mold as an important component of the environmental contribution to the development and pathogenesis of asthma leads to questions about possible interventions to prevent and/or attenuate mold-related health effects. In epidemiologic studies it is difficult to determine the species of mold that are the causative agents since many subjects are exposed to more than one mold. This lead us to develop a murine model of chronic mold exposure to examine the inflammatory phenotypes induced by individual molds and the mechanisms underlying those phenotypes. The work in this dissertation uses two molds that are common in the Ohio River Valley, Aspergillus versicolor and Cladosporium cladosporioides. In our model mice were repeatedly exposed to either A. versicolor or C. cladosporioides spores. The two molds induced distinct phenotypes and this effect was observed in both Balb/c and C57BL/6 strains. C. cladosporioides induced robust airway hyperresponsiveness (AHR), eosinophilia, and a predominately Th2 response, while A. versicolor induced a strong Th17 response and neutrophilic inflammation, but very mild AHR. Neutralization of IL-17A resulted in strong AHR and eosinophilic inflammation following A. versicolor exposure. In Dectin-1 deficient mice, A. versicolor exposure resulted in markedly attenuated IL-17A, robust AHR, and eosinophilic inflammation compared to wild type mice. A similar phenotype was observed in mice deficient in MyD88. In the absence of MyD88, IL-17A was attenuated in response to A. versicolor, and there was an induction of robust AHR and eosinophilic inflammation. In contrast, C. cladosporioides induced AHR and eosinophilic inflammation independent of IL-17A, Dectin-1, and MyD88. A. versicolor, but not C. cladosporioides, spores had increased exposure of beta-glucans on their surface and were able to bind Dectin-1. Thus, the host response to C. cladosporioides¿¿ was IL-17A- and Dectin1-independent, while Dectin-1 and IL-17A-dependent pathways were protective against the development of asthma after exposure to A. versicolor. Furthermore, exposure of beta-glucans on the surface of C. cladosporioides by heat killing the spores altered the immune response. Live C. cladosporioides induced robust airway hyperresponsiveness, eosinophilia, and a predominately Th2 response, while heat-killed C. cladosporioides induced a strong Th17 response and neutrophilic inflammation, but very mild AHR. Heat killing of C. cladosporioides spores effectively exposed beta-glucans on the surface of the spores and increased binding to Dectin-1. In the absence of Dectin-1, heat-killed spores induced a predominantly Th2 response analogous to live spores. Thus, the host immune response to C. cladosporioides is dependent on surface availability of beta-glucans rather than the total beta-glucan content. Finally, co-exposure with A. versicolor and HDM or C. cladosporioides induced synergy in the development of AHR and airway inflammation. Mice co-exposed to A. versicolor and HDM developed a mixed Th2/Th17 response. Thus, co-exposure results in the development of a phenotype that mimics severe asthma. These data demonstrate that not all molds are created equal. The difference in beta-glucan exposure accounts for the distinct inflammatory phenotypes induced by each mold. Further, co-exposure results in synergistic inflammatory responses.

Name thesis:degree_name

PhD

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Medicine: Immunology

Grantor dc:publisher

University of Cincinnati

Year dc:date

2012

Author dc:creator

• Mintz-Cole, Rachael A.

Contributors dc:contributor

• Hershey, Gurjit

• Immunology
• Cladosporium cladosporioides
• Aspergillus versicolor
• mold
• asthma

Statement dc:rights

• unrestricted
• This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.

Language dc:language

English

Repository record dc:identifier

http://rave.ohiolink.edu/etdc/view?acc_num=ucin1353951649

OAI identifier oai:identifier

oai:etd.ohiolink.edu:ucin1353951649