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。

• 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
• 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

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.

摘要 肠道真菌是微生物区系的重要组成部分，最近的研究揭示了它们的潜力 在调节炎症性疾病方面。对真菌的粘膜免疫在很大程度上是在口腔的背景下探索的， 皮肤、阴道或肺部感染。尽管如此，控制肠道真菌免疫的机制(真菌生物群) 仍然不为人所知。我们已经证明，编码抗真菌受体的人类基因的一个多态性 Dectin-1(CLEC7A)与溃疡性结肠炎的严重程度密切相关，在小鼠模型中， 结肠炎和肺过敏、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形成宿主免疫的一个重要因素。 作为粘膜免疫的中枢，胃肠道天生就有一种细胞机制 来识别这个身体部位的微生物群并与之相互作用。肠道中含有几个子集的 吞噬细胞，已知能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 在不同水平的CD11b中表达整合素CD103，以及表达高水平的肠道MNPs CX3CR1。CX3CR1+MNPs和CD103+DC具有诱导抗原特异性T辅助反应的潜能 肠道内的共生菌和病原菌。我们和其他人已经证明Dectin-1/CARD9轴是 在几个屏障位置诱导抗真菌Th17免疫至关重要，并可影响对 肠道真菌区系。然而，肠道吞噬细胞网络如何协调肠道真菌感知和免疫 对真菌生物群的影响目前尚不清楚。 越来越清楚的是，对微生物群的异常促炎反应是通过渗透 单核细胞在肠道炎症的发生发展中起着重要作用。我们的数据显示，肠道 具有巨噬细胞特征的单核巨噬细胞在限制真菌生长中起着重要作用 肠道过度生长，并可受到炎症环境的影响，进一步推动炎症。 我们进一步证明，CX3CR1+肠道单核巨噬细胞(MNPs)的一个特定亚群与骨质疏松症相互作用。 真正的肠道真菌可以触发对真菌的先天和获得性免疫反应。使用有条件的击倒在 活体模型、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 肠道影响健康状态和炎症性疾病。更好地理解肠道的相互作用 吞噬细胞与共生菌共生，将为更有针对性的发展提供机会 炎症性疾病的治疗方法。