The role of the GP2-IgA-microbiota interactome in intestinal homeostasis and disease

GP2-IgA-微生物相互作用组在肠道稳态和疾病中的作用

基本信息

  • 批准号:
    509089618
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    德国
  • 项目类别:
    WBP Fellowship
  • 财政年份:
  • 资助国家:
    德国
  • 起止时间:
  • 项目状态:
    未结题

项目摘要

The gut is inhabited by a vast population of symbiotic bacteria (microbiota) that are essential to host health, immune system development and maturation. The host immune system is in a constant and mutualistic dialogue with the microbiota - a dialogue that is essential for gut homeostasis. Therefore, both dysbiosis and inappropriate immune responses may drive the development of pathology such as inflammatory bowel disease (IBD). A key immune response mediating host-microbiota interaction and preventing dysbiosis is the secretion of immunoglobulin A (IgA) into the gut lumen. While the importance of adaptive IgA-responses to gut homeostasis is well established, the role and mechanisms of action of innate host-derived factors remain poorly studied. In this project we will investigate the role of glycoprotein 2 (GP2) - a host-derived protein that, like IgA, is secreted into the gut lumen, however, the in vivo functions of GP2 are largely unknown. Strikingly, GP2 is also a major autoantigen in IBD, although why GP2 becomes an autoantigen in IBD remains unclear. Our preliminary results show that GP2 binds to a large proportion of the microbiota in both mice and humans, that GP2-bound bacteria are co-associated with IgA (but not IgG) and that levels of GP2-binding correlate with IgA-binding. Furthermore, GP2-deficient mice show an altered IgA-binding profile and overall changes in microbiota composition, particularly in the small intestine. Based on these findings, we hypothesize that GP2 represents a key innate modulator of host-microbiota interactions and may play an important role in intestinal homeostasis. In this proposal we aim to characterize the underlying mechanism regulating GP2-interactions with the microbiota, ist role in IgA-microbiota interactions and the importance of these interactions in mucosal immunity, intestinal homeostasis and disease. To assess this, we will utilize a wide range of multidisciplinary approaches including multiparameter flow cytometry, immunohistochemistry, bacterial cell sorting and 16S rRNA sequencing and mass spectrometry. We will make use GP2-deficient mice and established intestinal inflammation models to examine how GP2, IgA and the microbiota interact (at a population and cellular level). Knowledge gained from mouse experiments will allow us to expand our analysis on samples from healthy and inflamed human gut. Finally, we will examine the mechanisms leading to the generation of GP2 autoantibodies in chronic intestinal inflammation. Collectively, we anticipate the results of this project to substantially further our understanding of how innate immune mechanisms may converge with adaptive mechanisms to affect intestinal homeostasis and disease and as such will have important implications for both clinical diagnosis and novel treatment approaches for IBD.
肠道中居住着大量的共生细菌(微生物群),这些细菌对宿主健康,免疫系统发育和成熟至关重要。宿主免疫系统与微生物群进行持续的互利对话-这种对话对于肠道内稳态至关重要。因此,生态失调和不适当的免疫反应都可能导致炎症性肠病(IBD)等病理学的发展。介导宿主-微生物群相互作用并防止生态失调的关键免疫应答是将免疫球蛋白A(伊加)分泌到肠腔中。虽然适应性IgA应答对肠道内稳态的重要性已经得到了很好的确立,但先天宿主衍生因子的作用和机制仍然研究不足。在这个项目中,我们将研究糖蛋白2(GP 2)的作用-一种宿主衍生的蛋白质,像伊加一样分泌到肠腔中,然而,GP 2的体内功能在很大程度上是未知的。引人注目的是,GP 2也是IBD中的主要自身抗原,尽管GP 2成为IBD中的自身抗原的原因尚不清楚。我们的初步结果表明,GP 2与小鼠和人类中大部分微生物群结合,GP 2结合的细菌与伊加(但不是IgG)共同相关,并且GP 2结合水平与IgA结合相关。此外,GP 2缺陷小鼠显示出IgA结合谱的改变和微生物群组成的总体变化,特别是在小肠中。基于这些发现,我们假设GP 2代表宿主-微生物群相互作用的关键先天调节剂,并可能在肠道内稳态中发挥重要作用。在这项提议中,我们的目标是表征调节GP 2与微生物群相互作用的潜在机制,它在IgA-微生物群相互作用中的作用以及这些相互作用在粘膜免疫、肠道稳态和疾病中的重要性。为了评估这一点,我们将利用广泛的多学科方法,包括多参数流式细胞术,免疫组织化学,细菌细胞分选和16 S rRNA测序和质谱。我们将使用GP 2缺陷小鼠和建立的肠道炎症模型来研究GP 2,伊加和微生物群如何相互作用(在群体和细胞水平上)。从小鼠实验中获得的知识将使我们能够扩展对健康和发炎的人类肠道样本的分析。最后,我们将研究导致慢性肠道炎症中GP 2自身抗体产生的机制。总的来说,我们预计该项目的结果将大大促进我们对先天免疫机制如何与适应性机制融合以影响肠道稳态和疾病的理解,因此将对IBD的临床诊断和新的治疗方法产生重要影响。

项目成果

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Dr. Johanna Kabbert其他文献

Dr. Johanna Kabbert的其他文献

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