Functional characterization of CARD9 genetic variants in fungal immunity

CARD9 遗传变异在真菌免疫中的功能表征

• 批准号: 10331807
• 负责人: Ramnik J Xavier
• 金额: $ 69.83万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-08 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10331807
• 关键词: Affect; Alleles; BCL10 gene; C Type Lectin Receptors; C-terminal; Candida; Carbohydrates; Cells; Chronic; Colitis; Communicable Diseases; Data; Dendritic Cells; Detection; Deubiquitination; Development; Disease; Disease susceptibility; Down-Regulation; Equilibrium; Exhibits; Gene Expression; Genes; Genetic Polymorphism; Genomics; Goals; Hereditary Disease; Host Defense; Human; Human Genetics; Immune; Immune response; Immunity; Individual; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Injury; Investigation; Life; Mediating; Minor; Molecular; Mucosa- associated lymphoid tissue lymphoma translocation protein-1; Mucous Membrane; Mutation; Mycoses; Natural Immunity; Patients; Penetrance; Persons; Phenotype; Phosphorylation; Population; Predisposition; Production; Receptor Signaling; Regulation; Reporting; Risk; Role; Sampling; Second Messenger Systems; Series; Signal Transduction; Signaling Protein; Skin; Splice-Site Mutation; Spondylitis; Surface; Systemic infection; Systems Biology; Ubiquitin; Ubiquitination; Work; congenital immunodeficiency; cytokine; disorder risk; experience; functional genomics; fungus; gene function; gene product; genetic variant; human disease; loss of function mutation; mouse model; novel; novel therapeutic intervention; pathogen; pathogenic fungus; promoter; protective allele; protein function; recruit; release of sequestered calcium ion into cytoplasm; response; small molecule; therapeutic target; tissue biomarkers

ABSTRACT Fungi are ubiquitous colonizers of skin and mucosal surfaces. While many individuals exhibit minor fungal outgrowth, millions of others experience systemic infections with life-threatening consequences. Polymorphisms in numerous genes have been associated with the ability of an individual to generate an inflammatory response to fungal pathogens. In many of these genes, rare high-penetrance alleles have been observed that strongly disrupt gene function, resulting in primary immunodeficiencies and an increase in infectious disease susceptibility. Additionally, common genetic variants have been reported in these genes that increase the risk of disease by modifying the activity or expression of the gene product to a small but significant degree. These genes offer a unique opportunity to understand how immune responses to pathogens are tuned to achieve an appropriate level of immune response. This hypothesis is well illustrated by the various phenotypes associated with different genetic variants of CARD9. CARD9 is a signaling protein that functions downstream of many C type lectin receptors (CLRs), which recognize carbohydrate moieties on fungi and other pathogens. Understanding how these human disease-related CARD9 mutations affect CARD9 functions will advance our understanding of fungal immunity. In Aim 1 of this proposal, we examine the role of Card9 ubiquitination on fungal detection by dendritic cells. In Aim 2, we will identify the molecular mechanisms controlling Card9 phosphorylation and their consequences for fungal detection. In Aim 3, we compare how Card9 genetic variants affect Candida infection and the development of colitis. Together, these aims will decipher the mechanistic basis of CARD9 regulation and characterize CARD9 genetic variants to identify novel molecular mechanisms with important roles in fungal defense and inflammation.

抽象的 真菌是无处不在的皮肤和粘膜表面的殖民者。尽管许多人表现出较小的真菌生长，但数以百万计的其他人会经历系统性感染，并带来威胁生命的后果。许多基因的多态性与个体对真菌病原体产生炎症反应的能力有关。在这些基因中的许多基因中，已经观察到罕见的高渗透等位基因强烈破坏基因功能，导致原发性免疫缺陷和感染性疾病敏感性的增加。此外，这些基因中已经报道了常见的遗传变异，从而通过将基因产物的活性或表达在很小但很大程度上来增加疾病的风险。这些基因提供了一个独特的机会来了解如何调整对病原体的免疫反应以达到适当水平的免疫反应。与Card9的不同遗传变异相关的各种表型很好地说明了这一假设。 Card9是一种信号蛋白，在许多C型凝集素受体（CLR）下游起作用，该蛋白质在真菌和其他病原体上识别碳水化合物部分。了解这些与人类疾病相关的Card9突变如何影响Card9功能将提高我们对真菌免疫的理解。在该提案的目标1中，我们研究了Card9泛素化对树突状细胞真菌检测的作用。在AIM 2中，我们将确定控制Card9磷酸化的分子机制及其对真菌检测的后果。在AIM 3中，我们比较了Card9遗传变异如何影响念珠菌感染和结肠炎的发展。这些目标共同解释了Card9调节的机械基础，并表征Card9遗传变异，以鉴定具有重要作用在真菌防御和炎症中重要作用的新型分子机制。

项目成果

USP15 Deubiquitinates CARD9 to Downregulate C-Type Lectin Receptor-Mediated Signaling.

• DOI: 10.4049/immunohorizons.2000036
• 发表时间: 2020-10-22
• 期刊: ImmunoHorizons
• 作者: Xu W;Rush JS;Graham DB;Cao Z;Xavier RJ
• 通讯作者: Xavier RJ