Dust-Induced Microbiome Changes Alter Allergic Immune Responses

灰尘引起的微生物组变化改变过敏性免疫反应

• 批准号: 8392346
• 负责人: Susan Veronica Lynch
• 金额: $ 24.93万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-06 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8392346
• 关键词: Address; Affect; Age; Allergens; Allergic; Allergic Disease; American; Animal Model; Animals; Antibodies; Antigen-Presenting Cells; Antigens; Applications Grants; Area; Asthma; Bone Marrow; Bone Marrow Cells; Canis familiaris; Cells; Cellular Structures; Child; Chimera organism; Chronic; Clinical; Collaborations; Communities; Country; Data; Dendritic Cells; Development; Dictyoptera; Disease; Dust; Elderly; Environment; Epidemiology; Exposure to; Extrinsic asthma; Flow Cytometry; Gene Expression; Gnotobiotic; Histology; Home environment; House Dust; Household; Human; Hypersensitivity; IgE; Immune; Immune response; In Vitro; Individual; Infant; Infant Development; Instruction; Investigation; Lead; Life; Link; Lung; Lung diseases; Lymphoid Cell; Measures; Modeling; Mucous body substance; Mus; Oral; Outcome; Ovalbumin; Pattern; Phenotype; Physiological; Population; Prevalence; Prevention strategy; Program Research Project Grants; Pulmonary Pathology; Relative (related person); Research; Research Personnel; Risk; Role; Sampling; Serum; Soil; Stem cells; T cell response; Testing; Toll-like receptors; Translating; airway hyperresponsiveness; allergic response; clinically relevant; cockroach allergen; cytokine; disease phenotype; eosinophilic inflammation; gastrointestinal; infancy; innovation; microbiome; mouse model; novel; pet animal; programs; research study; response

Allergic asthma is common in Westernized countries and its prevalence has increased greatly during the last century. Interestingly, recent research has shown that exposure to pets during infancy correlates with a lower risk of developing allergy and asthma in later life. In addition, data generated by the PPG investigators have demonstrated that pets can be associated with alterations to the microbiota in house dust. It is well known that soil and dust are ingested by children, and alterations in gut microbiome have been associated with risk for allergic asthma development. In order to further our understanding of the mechanisms that lead to the alterations observed clinically, this project has established and utilized models of pulmonary disease with exposure to dust from homes with dogs versus no pets. Using two different mouse models of allergic asthma (cockroach antigen and ovalbumin), we will study pulmonary immune responses after oral exposure to house dust using samples collected from homes with dogs and without pets. We will test the overall hypothesis that the composition of the dust microbiome from homes with dogs versus no pets differentially alters pulmonary immune responses during allergen exposure by changing the Gl microbiota or bacterial community composition (BCC), resulting in systemic changes in antigen presenting cell and bone marrow progenitor cell programming and allergic outcomes. To test this hypothesis, we will specifically focus on clinically relevant mechanisms involved in the ability of pulmonary-derived allergen responses to induce Th2 cytokines, mucus hypersecretion, physiologic changes (AHR), and changes in innate responses locally as well as systemically. Our studies will: 1) establish that exposure of mice to dust from homes with dogs versus no pets will result in differential changes in the Gl BCC, 2) demonstrate that the dog dust-altered gut microbiome alters pulmonary allergic responses, 3) establish that the dog dust-induced changes alter dendritic cell responses in the lung, 4) identify that changes in innate responses are a systemic effect by examining bone marrow cell responses, and 5) utilize innovative mouse models to derive the cellular mechanisms of the altered responses. BCC will be measured using the G3 PhyloChip. Thus, these studies, in close collaboration with the other projects in this PPG, will clarify a number of previously unexplored questions and will guide exploration into this novel area of research.

过敏性哮喘在西方国家很常见，在上个世纪其患病率大大增加。有趣的是，最近的研究表明，婴儿期接触宠物与晚年患过敏和哮喘的风险较低有关。此外，PPG研究人员生成的数据表明，宠物可能与室内灰尘中微生物群的改变有关。众所周知，土壤和灰尘被儿童摄入，肠道微生物组的改变与过敏性哮喘的发生风险有关。为了进一步了解导致临床观察到的变化的机制，该项目建立并利用了接触有狗和没有宠物的家庭灰尘的肺部疾病模型。使用两种不同的小鼠过敏性哮喘模型（蟑螂抗原和卵清蛋白），我们将研究肺部免疫反应后，口腔接触到室内灰尘使用的样品收集家庭与狗和没有宠物。我们将测试总体假设，即来自有狗的家庭与没有宠物的家庭的灰尘微生物组的组成通过改变GI微生物群或细菌群落组成（BCC）而在过敏原暴露期间差异性地改变肺免疫应答，从而导致抗原呈递细胞和骨髓祖细胞编程和过敏结果的系统性变化。为了验证这一假设，我们将特别关注临床相关机制，涉及肺源性过敏原反应诱导Th2细胞因子，粘液分泌过多，生理变化（AHR），以及局部和全身先天性反应的变化。我们的研究将：1）确定小鼠暴露于来自有狗的家庭与没有宠物的家庭的灰尘将导致GI BCC的差异性变化，2）证明狗尘改变的肠道微生物组改变肺过敏反应，3）确定狗尘诱导的变化改变肺中的树突细胞反应，4）通过检查骨髓细胞反应鉴定先天反应的变化是全身效应，和5）利用创新的小鼠模型来推导改变的反应的细胞机制。BCC将使用G3 PhyloChip测量。因此，这些研究与PPG中的其他项目密切合作，将澄清一些以前未探索的问题，并将指导探索这一新的研究领域。