Role of Fungal Microflora in Mucosal Tolerance/Immunity

描述（由申请人提供）：在过去的40年里，哮喘和过敏的发病率在西方化国家急剧上升（目前美国、英国、新西兰和澳大利亚有30%的学龄儿童患有哮喘）。这种增加背后的机制尚不清楚。然而，在这段时间内，哮喘发病率的惊人增长表明，遗传以外的因素在疾病的发展中起着重要作用。大量的人类流行病学研究表明，抗生素的使用或粪便菌群的改变与过敏的发生之间存在相关性。这一提议的假设是，微生物群在维持粘膜对吸入/吞咽抗原的耐受性方面起着核心作用，这可以防止对这些抗原产生过度的炎症反应（即过敏）。因此，微生物群的变化，包括真菌菌群（念珠菌）的生长增加，降低了粘膜耐受性，导致对吸入过敏原的过敏反应的发展。抗生素和饮食对微生物群的组成有重大影响。我们已经建立了一个动物模型来验证这一假设，我们对该模型的初步研究支持了微生物群改变可能是过敏性气道疾病发展的潜在机制这一概念。这项建议的具体目的如下：分析胃肠道中念珠菌存在和不存在的情况下停用抗生素后发生的微生物群重构动力学。2. 目的：确定不同念珠菌种类和分离株对破坏粘膜耐受性的影响，并确定粘膜耐受性缺陷的持续时间。3. 分析念珠菌“毒力”因子在念珠菌在胃肠道滞留期间破坏小鼠粘膜耐受的作用。4. 确定抗生素诱导的微生物群破坏是否会改变肺部抗原特异性调节性T细胞反应的发展。这些研究将为未来的人类研究提供基础科学基础，以了解如何以及为什么操纵微生物群（通过饮食或益生菌）可以改变或预防过敏。

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.