Dissecting the impact of immune environment on Candida albicans pathogenic potential in the gut

剖析免疫环境对肠道白色念珠菌致病潜力的影响

• 批准号: 10724531
• 负责人: Kyla Ost
• 金额: $ 46万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10724531
• 关键词: Adherence; Animal Model; Antibodies; Automobile Driving; Benign; Biology; Candida; Candida albicans; Cells; Colitis; Communities; Development; Disease; Environment; Foundations; Fungal Genes; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genetic Transcription; Goals; Health; Heterogeneity; Human; Hyphae; Immune; Immune response; Immunity; Immunoglobulin A; Immunological Models; Individual; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestines; Invaded; Investigation; Knowledge; Life; Life Style; Link; Maintenance; Microbe; Modeling; Morphology; Mucous Membrane; Mus; Pathogenesis; Pathogenicity; Pathway interactions; Persons; Phenotype; Population; Predisposition; Process; Recovery; Regulation; Risk; Role; Shapes; Study models; Testing; Time; Work; adaptive immune response; adaptive immunity; cell injury; cell type; commensal microbes; fungus; gut colonization; gut inflammation; gut microbiome; gut microbiota; immunological status; in vivo; member; microbial; microbial community; microbiome; microbiota; mouse model; murine colitis; novel; opportunistic pathogen; prevent; programs; targeted treatment

PROJECT SUMMARY The human gut microbiome harbors microbes with the capacity to cause infection or drive pathogenic inflammation. Immune status often determines risk for microbiome-associated disease, which is typically attributed to immune impacts on microbial community composition. But pathogenic or commensal lifestyles can also be dynamically regulated within individual microbes, and there is far less understood about immune impacts on microbial inherent pathogenic potential. Candida albicans is a morphologically and transcriptionally dynamic commensal fungus that can cause life-threatening infections and exacerbate pathogenic inflammation. The ability for C. albicans to cause disease depends on its phenotypic state. Of particular importance is the formation of hyphae, which are elongated cells specialized for adherence and invasion, and promote disease in both infection and inflammatory settings. Immune status is crucial for determining risk for C. albicans-associated disease and both immune deficiencies and active inflammation are linked to C. albicans pathogenesis. However, the role of immune environment on in vivo C. albicans pathogenic potential is not well understood. Here, I will investigate the impact of two human relevant immune environments on C. albicans pathogenic potential. Project 1 will focus on IgA regulation of C. albicans biology. Anti-C. albicans IgA antibodies are found in the gut of most people, and I previously found that C. albicans hyphae and associated effectors are heavily targeted by IgA during colonization. In mouse models, IgA targeting is associated with reduced hyphae and reduced capacity to exacerbate colitis. Here, I will interrogate mechanisms by which IgA regulates C. albicans biology in vivo using a mouse colonization model that permits investigation of immediate regulatory impacts of IgA targeting on C. albicans biology. Using this model, I will interrogate IgA impacts on C. albicans morphology and gene expression, which will include single cell transcriptional profiling to investigate gene expression in individual IgA-targeted cells. The goal of Project 2 is to define the impacts of inflammation on C. albicans pathogenic potential. Evidence from human IBD studies and mouse models of colitis suggest that this fungus exploits inflammation to bloom and perpetuate disease. Here, I will use a mouse model of intestinal colitis to define inflammation-dependent impacts on C. albicans morphology and transcriptional profile, with the goal of defining C. albicans pathways responsible for disease exacerbation. This proposal will reveal fundamental mechanisms by which immune environment regulates C. albicans biology and advance our understanding of how C. albicans becomes pathogenic in certain people. Broadly, these efforts will provide a foundation for our long-term goal of identifying targeted therapeutic strategies to prevent commensal C. albicans reservoirs from causing disease.

项目摘要 人类肠道微生物组含有能够引起感染或驱动病原体的微生物 炎症免疫状态通常决定微生物组相关疾病的风险， 这归因于免疫对微生物群落组成的影响。但致病性或病态的生活方式 在单个微生物中也是动态调节的，而对免疫的了解要少得多。 对微生物固有致病潜力的影响。白色念珠菌是一种形态学和转录 可导致危及生命的感染并加剧病原体的 炎症C.白念珠菌致病取决于其表型状态。特别 重要的是菌丝的形成，菌丝是专门用于粘附和侵入的细长细胞， 在感染和炎症环境中促进疾病。免疫状态对于确定 C.白色念珠菌相关疾病以及免疫缺陷和活动性炎症都与念珠菌有关。白色 发病机制免疫环境对体内C.白色念珠菌致病潜力不佳 明白在这里，我将研究两种人类相关的免疫环境对C。白色 致病潜力项目1将重点研究伊加对C.白色念珠菌生物学抗C白色念珠菌伊加 抗体存在于大多数人的肠道中，我以前发现C。白色念珠菌菌丝及相关 在定殖过程中，效应子被伊加高度靶向。在小鼠模型中，伊加靶向与 减少菌丝和降低恶化结肠炎的能力。在这里，我将询问伊加 调节C.使用小鼠定殖模型进行体内白念珠菌生物学研究， 伊加靶向对C.白色念珠菌生物学使用这个模型，我将询问伊加对C的影响。 白念珠菌形态和基因表达，其中将包括单细胞转录谱，以调查 单个IgA靶向细胞中的基因表达。项目2的目标是确定炎症的影响 对秀丽隐白色念珠菌致病潜力。来自人类IBD研究和结肠炎小鼠模型的证据表明， 这种真菌利用炎症繁殖并延续疾病。在这里，我将使用一个小鼠模型， 肠道结肠炎，以确定炎症依赖的影响，C.白色念珠菌形态学和转录 轮廓，目标是定义C。白色念珠菌途径负责疾病恶化。这项建议会 揭示了免疫环境调节C.白色念珠菌生物学和推进我们的 了解C。白色念珠菌在某些人中会致病。总的来说，这些努力将提供 为我们确定预防丙型肝炎的靶向治疗策略的长期目标奠定了基础。 白色念珠菌水库引起疾病。