Role of Fungal Microflora in Mucosal Tolerance/Immunity

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DESCRIPTION (provided by applicant): In the past 40 years, the rates of asthma and allergies have increased dramatically in westernized countries (>30% of school age children in the US, Great Britain, New Zealand and Australia currently have asthma). The mechanism(s) underlying this increase is unknown. However, this staggering increase in the incidence of asthma in this time frame indicates that factors beyond genetics play a major role in the development of the disease. Numerous epidemiologic studies in humans have shown a correlation between antibiotic use or altered fecal microflora and the development of allergies. The hypothesis of this proposal is that the microflora plays a central role in maintaining mucosal tolerance to inhaled/swallowed antigens, which prevents the development of over-exuberant inflammatory responses to these antigens (i. e. allergies). Thus, changes in microflora populations, including increased growth of fungal microflora (Candida), decrease mucosal tolerance resulting in the development of allergic responses to inhaled allergens. Antibiotics and diet have a major impact on the composition of the microflora. We have generated an animal model to test this hypothesis and our preliminary studies with this model support the concept that altered microflora can be a potential mechanism underlying the development of allergic airway disease. The specific aims of this proposal are the following: 1. To analyze the dynamics of microbiota reconstitution that occurs following the cessation of antibiotics in the presence and absence of Candida in the gastrointestinal tract. 2. To determine the effect of different Candida species and isolates on disrupting mucosal tolerance and to determine the duration of defective mucosal tolerance. 3. To analyze the contribution of Candida "virulence" factors in disrupting mucosal tolerance in mice during Candida persistence in the Gl tract. 4. To determine whether antibiotic-induced microbiota disruption alters the development of antigen-specific regulatory T cell responses for the lungs. These studies will provide the basic science foundation for future studies in humans for understanding how and why manipulation of the microflora (by diet or probiotics) can alter or prevent allergies.