Regulation and function of mucosal IgA immune responses to mycobiota in the gut.

肠道菌群粘膜 IgA 免疫反应的调节和功能。

• 批准号: 10279256
• 负责人: ILIYAN Dimitrov ILIEV
• 金额: $ 58.49万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10279256
• 关键词: Affect; Antibodies; Antibody Repertoire; Antibody Response; Antifungal Agents; B-Lymphocytes; Bacteria; Binding; Biological; Biological Models; CX3CR1 gene; Candida; Candida albicans; Catalogs; Collection; Data; Defect; Development; Disease; Epitopes; Equilibrium; Event; Fungal Components; Gastrointestinal tract structure; Genes; Genetic; Genetic Polymorphism; Germ-Free; Health; Homeostasis; Human; Hyphae; Immune response; Immunity; Immunoglobulin A; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestinal Diseases; Intestines; Invaded; Knock-out; Lead; Link; Lymphoid Tissue; Measures; Metabolic; Microbe; Mouse Strains; Mucosal Immunity; Mucous Membrane; Mus; Mycoses; Organism; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Phagocytes; Play; Population; Process; Property; Regulation; Reporter; Role; SYK gene; Scanning; Secondary to; Secretory Immunoglobulin A; Site; Specificity; Surface; Techniques; Testing; Toxin; Virulence Factors; Virus; Work; Yeasts; cell type; commensal bacteria; computational platform; conditional knockout; crosslink; dectin 1; deep sequencing; dysbiosis; fractalkine receptor; fungal microbiota; fungus; gastrointestinal; gut colonization; gut microbiota; immunogenic; in vivo Model; inflammatory disease of the intestine; intestinal barrier; intestinal epithelium; member; microbial; microbiota; mouse model; novel; prevent; response; sequencing platform

Abstract Immunoglobulin A (IgA) is prominently secreted at mucosal surfaces and coats a fraction of the intestinal bacterial microbiota. In health and disease, secretory IgA (sIgA) binding influences intestinal immunity and homeostasis by crosslinking microbiota in the lumen to prevent encroachment on the intestinal epithelium, shuttling bound microbes to secondary lymphoid tissues, and directly modulating microbial metabolic activity. Aside from the “natural” polyreactive IgA detectable in germ-free mice, sIgA is predominantly gut colonization dependent. The identification of immunogenic commensal bacteria and their specific IgA epitopes have further elucidated our understanding of the mechanisms governing gastrointestinal balance and how dysbiosis can drive intestinal pathologies. Meanwhile, the potential involvement of the fungal component of the gut microbiota (mycobiota) in these processes is largely unknown. Only recently have intestinal fungi been recognized as a factor contributing to events associated with inflammatory disease or response to therapy prompting multiple questions regarding the development of antifungal mucosal antibody responses, their specificity, and mechanisms of induction in the gut. In recent work, we have shown that polymorphisms in the Dectin-1 gene (CLEC7A) or the fractalkine receptor gene CX3CR1 are associated with defects in antifungal immunity in Inflammatory Bowel Disease (IBD) patients, and notably the latter leading to gut fungal overgrowth and substantial decrease of antifungal antibodies. In preliminary studies we unexpectedly identified a broad range of fungal organisms that were targeted by sIgA antibodies. Hyphal formation is a primary mechanism used by many dimorphic fungi to invade and survive within their hosts. Notably we found that mycobiota aggravated intestinal damage and inflammation is dependent upon hyphae-produced virulence factors that are targets of sIgA. These preliminary data support the overall hypothesis that antifungal sIgA antibody responses are naturally induced by specific gut mycobiota species and act against fungi-produced factors to play a key role in mucosal immunity by averting direct contact of fungi with the intestinal epithelium to prevent intestinal barrier damage and related gut inflammation. We will investigate this hypothesis both in vitro and in in vivo models, aided by deep sequencing and computational platforms, and genetically modified fungal strains. We will determine IgA-reactive gut mycobiota and fungal morphotypes involved in the induction of antifungal sIgA antibodies and will make use of several model systems to define the functional role of antifungal sIgA in gut.

摘要 免疫球蛋白A(IgA)主要分泌在粘膜表面，覆盖一部分肠道。 细菌微生物区系。在健康和疾病中，分泌型IgA(SIgA)结合影响肠道免疫和 通过在管腔内连接微生物群来防止对肠道上皮的侵蚀来实现动态平衡， 将结合的微生物穿梭到次级淋巴组织，并直接调节微生物的代谢活动。 除了在无菌小鼠体内检测到的“天然”多反应性IgA外，SIgA主要是肠道定植。 依附的。免疫原性共生菌及其特异性IgA表位的鉴定 阐明了我们对胃肠道平衡调节机制的理解，以及生物失调是如何驱动 肠道病理。同时，肠道微生物区系中真菌成分的潜在参与 (真菌生物群)在这些过程中的作用在很大程度上是未知的。直到最近，肠道真菌才被认为是一种 导致与炎症性疾病相关的事件的因素或对治疗的反应促使 关于抗真菌粘膜抗体反应的发展、其特异性和 肠道中的诱导机制。在最近的工作中，我们已经证明Dectin-1基因的多态 (CLEC7A)或Fractalkine受体基因CX3CR1与抗真菌免疫缺陷有关 炎症性肠病(IBD)患者，特别是后者导致肠道真菌过度生长和 抗真菌抗体大幅下降。在初步研究中，我们出人意料地发现了广泛的 以SIgA抗体为靶标的真菌生物体。菌丝形成是许多人使用的主要机制 侵入并在宿主体内生存的二相性真菌。值得注意的是，我们发现霉菌群加重了肠道 损伤和炎症依赖于菌丝产生的毒力因子，而这些因子是SIgA的靶标。这些 初步数据支持总体假设，即抗真菌SIgA抗体反应是由 肠道真菌菌群和抗真菌产生的因子在粘膜免疫中发挥关键作用 避免真菌与肠道上皮直接接触以预防肠道屏障和相关肠道的损伤 发炎。我们将在体外和体内模型中研究这一假说，并辅以深度测序。 和计算平台，以及转基因真菌菌株。我们将测定免疫球蛋白A反应肠道 参与诱导抗真菌SIgA抗体的真菌生物群和真菌形态类型，并将利用 几个模型系统来确定抗真菌SIgA在肠道中的功能作用。