Mononuclear phagocyte networks in mycobiota regulation and antifungal immunity.

菌群调节和抗真菌免疫中的单核吞噬细胞网络。

基本信息

批准号：
10611944
负责人：
ILIYAN Dimitrov ILIEV
金额：
$ 54.03万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10611944
关键词：
Affect Aggravated Colitis Antibody Formation Antifungal Agents Antigens Bacteria Bacterial Infections C Type Lectin Receptors CX3CR1 gene Candida Candida albicans Cells Characteristics Chronic Colitis Collection Communities Coupled DNA Sequence Alteration Data Defect Dendritic Cells Development Disease Disease Outcome Engineering Evolution Fungal Antigens Gastrointestinal tract structure Genes Genetic Genetic Polymorphism Germ-Free Growth Health Homeostasis Human Hypersensitivity ITGAM gene Immune Immunity In Vitro Individual Infectious Skin Diseases Infiltration Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Innate Immune Response Integrins Interleukin-10 Intestinal Diseases Intestines Intrinsic factor Knock-out Knockout Mice Knowledge Lead Lung Lung infections Macrophage Mediating Modeling Mononuclear Mucosal Immunity Mus Natural Immunity Pathology Patients Phagocytes Pharmaceutical Preparations Phenotype Play Population Pulmonary Inflammation Rag1 Mouse Receptor Signaling Regulation Regulatory T-Lymphocyte Resolution Role Severities Shapes Side Site T-Lymphocyte Testing Transgenic Organisms Ulcerative Colitis Virus Work adaptive immune response adaptive immunity bacterial community chemokine commensal bacteria computational pipelines computational platform conditional knockout cytokine dectin 1 defined contribution dextran sulfate sodium induced colitis dysbiosis experimental study fractalkine receptor functional disability fungal microbiota fungus genome sequencing gut bacteria gut inflammation in vivo in vivo Model inflammatory milieu inflammatory modulation insight microbiota monocyte mouse model murine colitis mycobiome oral infection pathogenic bacteria pathogenic fungus receptor receptor-mediated signaling response targeted treatment vaginal infection whole genome

项目摘要

Abstract Intestinal fungi are an important component of the microbiota, and recent studies have unveiled their potential in modulating inflammatory disease. Mucosal immunity to fungi has been largely explored in the context of oral, skin, vaginal or lung infection. Nonetheless, the mechanisms governing immunity to gut fungi (mycobiota) remain unknown. We have shown that a polymorphism in the human gene encoding the anti-fungal receptor Dectin-1 (CLEC7A) is strongly associated with severity of ulcerative colitis and that, in a mouse models of colitis and lung allergy, fungal dysbiosis can contribute to intestinal and lung inflammation. This suggests that intestinal immunity to fungi may be an important factor in shaping host immunity. As a central hub of mucosal immunity, the gastrointestinal tract is naturally equipped with a cellular machinery to recognize and interact with the microbiota populating this body site. The intestines harbor several subsets of phagocytes, which are known to respond to bacterial infections or to fluctuations in commensal bacterial communities. These intestinal phagocyte subsets comprise of conventional dendritic cells (DCs), most of which express the integrin CD103 albeit different levels of CD11b, and intestinal MNPs which express high levels of CX3CR1. CX3CR1+ MNPs and CD103+ DCs have the potential to induce antigen specific T helper responses to commensal and pathogenic bacteria in the gut. We and others have shown that Dectin-1/ CARD9 axis is crucial for the induction of antifungal Th17 immunity at several barrier sites and can affect responses toward intestinal mycobiota. However how intestinal phagocyte networks coordinate gut fungal sensing and immunity to mycobiota is currently unknown. It is becoming increasingly clear that an aberrant pro-inflammatory response to microbiota by infiltrating monocytes plays a role in the development of intestinal inflammation. Our data show that intestinal mononuclear phagocytes with characteristics of macrophages play an important role in limiting fungal overgrowth in the gut, and can be influenced by the inflammatory environment to further propel inflammation. We further show that a specific subset of CX3CR1+ gut mononuclear phagocytes (MNPs) interacts with bona- fide gut fungi to trigger innate and adaptive immune responses to fungi. Employing conditional knock out in vivo models, model fungal strains, high-throughput platforms for fungal and bacterial sequencing, targeting of fungi with drugs, and computational pipelines, we will define how phagocytes control immunity to fungi in the gut to influence states of health and inflammatory disease. Better understanding of the interaction of intestinal phagocytes with commensal fungi, would provide an opportunity for the development of more targeted therapies for inflammatory diseases.

抽象的肠道真菌是微生物群的重要组成部分，最近的研究揭示了它们的潜力调节炎症性疾病。对真菌的粘膜免疫已在口腔、皮肤、阴道或肺部感染。尽管如此，控制肠道真菌（真菌群）免疫的机制仍然未知。我们已经证明编码抗真菌受体的人类基因存在多态性 Dectin-1 (CLEC7A) 与溃疡性结肠炎的严重程度密切相关，并且在小鼠模型中结肠炎和肺部过敏、真菌失调可导致肠道和肺部炎症。这表明肠道对真菌的免疫可能是塑造宿主免疫的重要因素。胃肠道作为粘膜免疫的中枢，天然配备有细胞机器识别该身体部位的微生物群并与之互动。肠道有几个子集吞噬细胞，已知会对细菌感染或共生细菌的波动做出反应社区。这些肠道吞噬细胞亚群由传统的树突状细胞 (DC) 组成，其中大部分表达整合素 CD103，尽管 CD11b 的水平不同，并且肠道 MNP 表达高水平的 CX3CR1。 CX3CR1+ MNP 和 CD103+ DC 具有诱导抗原特异性 T 辅助细胞反应的潜力肠道内的共生菌和致病菌。我们和其他人已经证明 Dectin-1/CARD9 轴是对于在几个屏障位点诱导抗真菌 Th17 免疫至关重要，并且可以影响对肠道菌群。然而，肠道吞噬细胞网络如何协调肠道真菌感知和免疫目前未知。越来越清楚的是，微生物群的异常促炎症反应是通过渗透单核细胞在肠道炎症的发展中发挥作用。我们的数据表明，肠道具有巨噬细胞特征的单核吞噬细胞在限制真菌中发挥重要作用肠道内过度生长，并且可能受到炎症环境的影响，进一步促进炎症。我们进一步表明，CX3CR1+肠道单核吞噬细胞（MNP）的特定子集与真正的相互作用相信肠道真菌能够引发对真菌的先天和适应性免疫反应。采用条件淘汰体内模型、真菌菌株模型、真菌和细菌测序的高通量平台、靶向真菌与药物和计算管道，我们将定义吞噬细胞如何控制对真菌的免疫肠道影响健康状况和炎症性疾病。更好地了解肠道相互作用吞噬细胞与共生真菌的结合，将为开发更有针对性的炎症性疾病的治疗。