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.

摘要