Commensal Candida albicans primed Th17 immunity

共生白色念珠菌引发 Th17 免疫

• 批准号: 10586245
• 负责人: Richard John Bennett
• 金额: $ 81.23万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586245
• 关键词: Address; Antibiotics; Antigens; Architecture; Automobile Driving; Bacteria; Blood Circulation; CD4 Positive T Lymphocytes; Candida albicans; Cell Communication; Cell Wall; Cells; Cellular Immunology; Clinical; Communicable Diseases; Data; Defect; Engineering; Epithelial Cells; Eukaryota; Gastrointestinal tract structure; Genes; Grant; Health Promotion; Human; IL17 gene; Immune; Immune response; Immunity; Immunocompetent; Immunocompromised Host; Immunologic Deficiency Syndromes; Immunologic Stimulation; Immunologics; Individual; Infection; Inflammation; Inflammatory Bowel Diseases; Intestines; Intravenous; Investigation; Job' s Syndrome; Knowledge; Laboratories; Leukocytes; Life; Ligands; Mannans; Microbe; Modeling; Molecular; Morphology; Mucous Membrane; Mus; Mycoses; Neutropenia; Oxidases; Pathogenesis; Pattern Recognition; Pattern recognition receptor; Population; Predisposition; Production; Property; Publishing; Reactive Oxygen Species; Recombinants; Research Personnel; Risk Factors; Role; STAT3 gene; Signal Transduction; Specificity; Staphylococcus aureus; Structure; Symbiosis; Systemic infection; T-Lymphocyte; Taxonomy; The science of Mycology; Tissues; Toxin; Variant; Virulence; Work; Yeasts; beta-Glucans; cellular engineering; commensal bacteria; commensal microbes; dysbiosis; experimental study; extracellular; fungus; gastrointestinal; gut colonization; gut dysbiosis; host-microbe interactions; immunogenic; intestinal epithelium; lens; microbial; mouse model; mutant; neutrophil; pathobiont; pathogen; pathogenic bacteria; public health relevance; reconstitution; response; trait

Abstract. The human intestine harbors an estimated 100 trillion microbes that are increasingly recognized to promote health through tonic immune stimulation. These include innocuous commensal microbes along with pathobionts - those capable of causing gut dysbiosis or invasive infection. Most of what we currently understand about host-microbe commensalism has been evaluated through the lens of bacteria. However, microbes from other taxonomic domains, including eukaryotes, also ubiquitously colonize mucosal tissues and yet our understanding of how these microbes establish commensalism and drive immunological changes remains rudimentary. This gap in knowledge is especially significant for the most common fungal pathobiont Candida albicans, which can translocate out of the gastrointestinal (GI) tract and cause life-threatening systemic infection, particularly in immunocompromised individuals. To address these fundamental gaps in knowledge, an instructive model of C. albicans intestinal colonization in mice was developed. Recombinant C. albicans cells were engineered to express defined model antigens and used to establish colonization so that T cells with surrogate C. albicans specificity could be identified. Using this model, we show that C. albicans cells colonizing the GI tract result in action at a distance - they drive the systemic accumulation of fungal-specific Th17 CD4+ T cells. These T cells work together with IL-17 and activated neutrophils to provide protection against a systemic infection by C. albicans as well as by extracellular bacterial pathogens. These results highlight the protective benefits of commensal C. albicans cells residing in the GI tract, and suggest that co-evolution with this species has led to a mutually beneficial relationship. However, important questions remain as to how C. albicans cells in the gut prime systemic immune responses, and how Th17 signals can be triggered without excessive inflammation. This line of investigation builds upon exciting preliminary data generated together by the laboratories of Dr. Way and Dr. Bennett, two investigators with complementary expertise in clinical infectious disease/cellular immunology and mycology/fungal pathogenesis, respectively. This proposal will address the molecular and cellular mechanisms by which C. albicans cells interact with mucosal host tissues to drive gut local and systemic immunity through the following specific aims: (1) Define how C. albicans morphological changes drive systemic Th17 immunity, (2) Establish the fungal ligand and host pattern recognition receptor(s) that prime systemic Th17 immunity, and (3) Investigate the role of reactive oxygen species and Duox2 (Dual Oxidase 2) for local and Th17 immunity primed by C. albicans cells. Each of these specific aims is supported by extensive published and unpublished preliminary data. Successful completion of these aims will shed light on the important symbiosis between fungal commensal and mammalian host, and the mechanisms responsible for priming systemic Th17 immunity through intestinal stimulation.

抽象的。人类肠道拥有大约100万亿微生物，越来越多地认识到 通过补品免疫刺激促进健康。这些包括无害的共生微生物以及 病原体 - 能够引起肠道营养不良或浸润性感染的人。我们目前了解的大多数 关于宿主 - 微叶片的共生主义已通过细菌的晶状体进行了评估。但是，微生物来自 其他分类领域，包括真核生物，也普遍存在粘膜组织定居，但我们 了解这些微生物如何建立相等主义并驱动免疫学变化仍然存在 基本。知识的差距对于最常见的真菌病原体念珠菌尤其重要 白色疾病可以从胃肠道（gi）区域转移并引起威胁生命的全身感染， 特别是在免疫功能低下的个体中。为了解决知识中的这些基本差距 在小鼠中开发了白色念珠菌肠道定植的模型。重组白色念珠菌细胞是 设计为表达定义的模型抗原并用于建立定殖，以便具有替代的T细胞 可以识别白色念珠菌的特异性。使用此模型，我们表明白色念珠菌细胞定居于胃肠道 导致距离的作用 - 它们推动了真菌特异性TH17 CD4+ T细胞的全身积累。这些 T细胞与IL-17一起工作，并激活中性粒细胞，以防止通过 白色念珠菌以及细胞外细菌病原体。这些结果突出了保护性的好处 位于胃肠道中的共生白色念珠菌细胞，并表明与该物种的共同进化已导致 互惠关系。但是，关于白色念珠菌细胞如何在肠道中仍然存在的重要问题 系统性免疫反应以及如何触发TH17信号而不会过多发炎。这线 调查的基于Way博士和博士实验室共同产生的令人兴奋的初步数据。 贝内特（Bennett），两位在临床传染病/细胞免疫学和 真菌学/真菌发病机理。该建议将解决分子和细胞机制 白色念珠菌细胞与粘膜宿主组织相互作用，通过 以下具体目的：（1）定义白色念珠菌形态变化如何驱动全身性TH17免疫，（2） 建立最优质全身TH17免疫的真菌配体和宿主模式识别受体，以及（3） 研究活性氧和DUOX2（双氧化酶2）在局部和Th17免疫的作用 由白色念珠菌细胞。这些特定目标中的每一个都受到广泛发表和未发表的初步的支持 数据。这些目标的成功完成将阐明真菌共生之间的重要共生 和哺乳动物宿主，以及负责通过肠道启动系统性Th17免疫的机制 刺激。