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: 10386810
• 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/10386810
• 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; Fungal Antigens; Gastrointestinal tract structure; Genes; Genetic; Genetic Polymorphism; Germ-Free; Health; Homeostasis; Human; Hypersensitivity; ITGAM gene; Immune; Immune System Diseases; Immunity; Impairment; In Vitro; Individual; Infectious Skin Diseases; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Integrins; Interleukin-10; Intestinal Diseases; Intestines; Intrinsic factor; Knock-out; Knowledge; Lead; Lung; Lung infections; 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; fungal microbiota; fungus; genome sequencing; gut bacteria; gut inflammation; in vivo; in vivo Model; inflammatory milieu; insight; macrophage; 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。对真菌的粘液免疫在很大程度上是在口腔， 皮肤、阴道或肺部感染。尽管如此，控制肠道真菌（真菌生物群）免疫的机制 仍然未知。我们已经证明，人类基因编码抗真菌受体的多态性 Dectin-1（CLEC 7A）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，真菌生态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重要因素。 作为粘膜免疫的中枢，胃肠道天然地配备有细胞机械 来识别并与这个身体部位的微生物群相互作用。肠道内有几个亚类 巨噬细胞，已知其对细菌感染或肠道细菌的波动作出反应。 社区.这些肠道吞噬细胞亚群包括常规树突状细胞（DC），其中大多数 表达整合素CD 103，尽管CD 11b的水平不同，而表达高水平整合素CD 103的肠MNP CX3CR1。CX 3CR 1 + MNP和CD 103 + DCs具有诱导抗原特异性T辅助细胞应答的潜力 肠道中的细菌和致病菌。我们和其他人已经表明，Dectin-1/CARD 9轴是 对于在几个屏障部位诱导抗真菌Th 17免疫至关重要，并可影响对 肠道菌群然而，肠道吞噬细胞网络如何协调肠道真菌传感和免疫 目前还不清楚。 越来越清楚的是，通过浸润微生物群而对微生物群产生的异常促炎反应可能是导致炎症的主要原因。 单核细胞在肠道炎症的发展中起作用。我们的数据显示， 具有巨噬细胞特性的单核吞噬细胞在限制真菌感染中起重要作用， 肠道中的过度生长，并且可以受到炎症环境的影响以进一步推动炎症。 我们进一步表明，CX 3CR 1+肠道单核吞噬细胞（MNP）的一个特定子集与博纳-卡那霉素相互作用。 真正的肠道真菌引发先天性和适应性免疫反应的真菌。采用条件敲除法 体内模型，模型真菌菌株，用于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免疫真菌中， 肠道影响健康状况和炎症性疾病。更好地理解肠道的相互作用 吞噬细胞与真菌，将提供一个机会，发展更有针对性的 炎症性疾病的治疗。