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: 10623294
• 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/10623294
• 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; Growth; Health; Homeostasis; Human; Hyphae; IgA Deficiency; Immune response; Immunity; Immunoglobulin A; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Intestinal Diseases; Intestines; Invaded; Knock-out; Knockout Mice; 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 inflammation; gut microbiota; immunogenic; in vivo Model; intestinal barrier; intestinal epithelium; member; microbial; microbiota; mouse model; novel; prevent; response; sequencing platform; treatment response

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.

抽象的 免疫球蛋白A（IgA）在粘膜表面显着分泌，涂层一小部分 细菌菌群。在健康和疾病中，秘密IGA（SIGA）结合影响肠道免疫学和 稳态通过在管腔中交联菌群，以防止对肠上皮的侵占 将结合的微生物穿上二次淋巴组织，并直接调节微生物代谢活性。 除了可在无菌小鼠中检测到的“天然”多氧化IGA外，Siga主要是肠道化的 依赖。免疫原性细菌及其特异性IgA表位的鉴定进一步 阐明了我们对管理胃肠道平衡机制的理解以及营养不良如何驱动 肠道病理。同时，肠道菌群的真菌成分的潜在参与 （Mycobiota）在这些过程中，在很大程度上是未知的。直到最近才有肠道真菌被认为是 导致与炎症性疾病或对治疗的反应有关的事件的因素促使多重 有关抗真菌粘膜抗体反应的发展，其特异性和 肠道诱导机制。在最近的工作中，我们表明Dectin-1基因中的多态性 （CLEC7A）或分面受体基因CX3CR1与抗真菌免疫缺陷有关 炎症性肠病（IBD）患者，尤其是后者导致肠道真菌过度生长和 抗真菌抗体的大幅下降。在初步研究中，我们意外地确定了广泛的 由SIGA抗体靶向的真菌生物。菌丝形成是许多主要机制 二态真菌入侵并在宿主中生存。值得注意的是，我们发现Mycobiota聚集了肠道 损伤和炎症取决于菌丝产生的病毒因子，这些病毒因子是SIGA的靶标。这些 初步数据支持了总体假设，即抗真菌SIGA抗体反应自然诱导 特定的肠道菌Mycobiota规格并针对真菌产生的因素采取行动，可通过 避免真菌与肠上皮的直接接触，以防止肠道屏障损伤和相关肠道 炎。我们将在体外和体内模型中研究这一假设，并通过深度测序 和计算平台以及转基因的真菌菌株。我们将确定IgA反应性抓地力 抗真菌SIGA抗体涉及的菌根和真菌形态型 定义抗真菌SIGA在肠道中的功能作用的几种模型系统。