Nlrp3 inflammasome signaling in immune responses to Candida albicans

Nlrp3 炎症小体信号在白色念珠菌免疫反应中的作用

• 批准号: 8239527
• 负责人: Fayyaz S. Sutterwala
• 金额: $ 37.13万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-04 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8239527
• 关键词: Abbreviations; Address; Affect; Agonist; Antigen-Presenting Cells; Apoptosis; BIR Domain; Baculoviruses; Binding; Biology; Bone Marrow; C Type Lectin Receptors; CD4 Positive T Lymphocytes; Candida; Candida albicans; Caring; Caspase; Caspase-1; Cathepsins B; Cells; Collaborations; Complex; Cysteine Protease; Data; Dendritic Cells; Development; Disease; Eagles; Environment; Epithelial; Etiology; Event; Family member; Formalin; Freund' s Adjuvant; Gene Targeting; Generations; Heating; Hyphae; Immune; Immune response; Immune system; Immunocompromised Host; Immunologic Receptors; Infection; Inflammation; Inflammatory Response; Interferons; Interleukin-1 Receptors; Interleukin-12; Interleukin-17; Interleukins; Intervention; Invaded; Knowledge; Letters; Leucine-Rich Repeat; Life; Light; Mediating; Medical; Mitochondria; Modality; Molecular; Morbidity - disease rate; Mucocutaneous Candidiasis; Mucous Membrane; Multiprotein Complexes; Mus; Mycoses; Nucleotides; Opportunistic Infections; Organism; Ovalbumin; Oxides; Pathogenesis; Pathway interactions; Pattern; Pattern recognition receptor; Phosphate Buffer; Play; Predisposition; Principal Investigator; Process; Production; Protein Tyrosine Kinase; Proteins; Public Health; RNA Helicase; Reactive Oxygen Species; Resolution; Role; Saline; Sepsis; Serum; Shapes; Signal Transduction; Sterility; Stimulus; Stress; Surface; T cell differentiation; TNF gene; Toll-like receptors; Tumor Necrosis Factor-alpha; Universities; Yeasts; adaptive immunity; combat; cytokine; diphenyleneiodonium chloride; experience; fetal; in vivo; insight; killings; macrophage; marenostrin; mortality; mutant; neutrophil; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; pathogen; patient population; programs; prophylactic; public health relevance; receptor; response; secretion process

DESCRIPTION (provided by applicant): C. albicans is a successful fungal commensal, highly adapted to survive on host surfaces such as mucosal tissue where it asymptomatically colonizes epithelial surfaces. C. albicans can also cause severe opportunistic infections particularly in immunocompromised patients ranging from mucocutaneous candidiasis to bloodstream infections. Even with optimal medical care there is still substantial mortality and morbidity associated with invasive fungal disease. In order to develop new therapeutic modalities directed at fungal pathogens a detailed understanding of the innate and adaptive immune pathways involved in control of pathogens such as C. albicans are required. In this proposal we will examine the role of the nucleotide-binding domain leucine-rich repeat containing receptor (NLR) family member Nlrp3 in recognition and response to infection with C. albicans. In macrophages Nlrp3 is activated in a multiprotein complex called the inflammasome in response to a wide variety of stimuli. The activation of the Nlrp3 inflammasome ultimately results in the activation of the cysteine protease caspase-1 and its processing and secretion of proinflammatory cytokines. C. albicans activates caspase-1 in an Nlrp3-dependent manner leading to the release of interleukin (IL)-12. Nlrp3-deficient mice also demonstrate increased susceptibility to infection with C. albicans in vivo. This proposal outlines three novel aims that will examine the molecular mechanism involved in activation of Nlrp3 by C. albicans. In Aim 1 the initial priming step required for Nlrp3 inflammasome activation in response to C. albicans will be addressed by determining if signaling mediated through Syk/Card9 is required for Nlrp3 inflammasome activation. In Aim 2 we will utilize gene targeted mice to determine if reactive oxygen species and cathepsin B play a role in C. albicans-induced activation of the Nlrp3 inflammasome. We will also identify Candida specific factors expressed during yeast-hyphae transition that are directly sensed by the Nlrp3 inflammasome. In Aim 3 we will examine how the Nlrp3 inflammasome shapes subsequent adaptive immune responses following in vivo infection with C. albicans and in particular if the development of IL-17 producing Th17 cells is dependent on the presence of Nlrp3. Successful completion of the proposed studies will provide a molecular understanding of how C. albicans activates the Nlrp3 inflammasome, and will substantially augment our knowledge of how the immune system controls fungal pathogens. Furthermore, new insights into the pathogenesis of C. albicans that result from these studies may suggest novel therapeutic approaches to combating this pathogen. PUBLIC HEALTH RELEVANCE: Candida albicans is a fungal pathogen that causes a wide variety of opportunistic infections, particularly in hospitalized patient populations where it is responsible for significant morbidity and mortality. Understanding how this pathogen interacts with and evades the immune system will help us identify new therapeutic targets to treat fungal infections and is hence directly relevant to public health. Our studies will focus on how the cytosolic pattern recognition receptor Nlrp3 is activated by Candida albicans and how this shapes subsequent immune responses by the host. In addition the information gained from the proposed studies will also shed light on the pathogenesis of other fungal organisms.

描述（由申请人提供）：白色念珠菌是一种成功的真菌共生，高度适应于宿主表面（例如粘膜组织），在粘膜组织中无效地将上皮表面定居。白色念珠菌还会引起严重的机会感染，特别是在免疫功能低下的患者中，从粘膜皮肤念珠菌病到血流感染。即使有最佳的医疗保健，仍然存在与侵入性真菌疾病有关的大量死亡和发病率。为了开发针对真菌病原体的新治疗方法，需要对需要控制病原体（例如白色念珠菌）的先天和适应性免疫途径的详细理解。在此提案中，我们将研究含有含核苷酸片的亮氨酸重复（NLR）家族成员NLRP3在识别和对白色念珠菌感染的反应中的作用。在巨噬细胞中，NLRP3在一种称为炎症体的多蛋白络合物中被激活，以响应各种刺激。 NLRP3炎性体的激活最终导致半胱氨酸蛋白酶caspase-1的激活及其促炎细胞因子的加工和分泌。白色念珠菌以NLRP3依赖性方式激活caspase-1，导致白介素（IL）-12的释放。 NLRP3缺乏的小鼠还表明，体内白色念珠菌感染的敏感性增加。该提案概述了三个新颖的目标，该目标将检查白色念珠菌与NLRP3激活有关的分子机制。在AIM 1中，通过确定是否需要通过SYK/CARD9介导的NLRP3炎性体激活需要的信号传导来解决NLRP3炎性体激活所需的初始启动步骤。在AIM 2中，我们将利用靶向小鼠的基因来确定活性氧和组织蛋白酶B是否在白色念珠菌诱导的NLRP3炎症体激活中起作用。我们还将确定在酵母流过渡期间表达的念珠菌特异性因素，而NLRP3炎性体直接感受到。在AIM 3中，我们将研究NLRP3炎性体形状在体内感染白色念珠菌后随后的适应性免疫反应如何，尤其是是否依赖于NLRP3的存在。成功完成拟议的研究将对白色念珠菌如何激活NLRP3炎性体的分子理解，并大大增强我们对免疫系统如何控制真菌病原体的了解。此外，这些研究引起的白色念珠菌发病机理的新见解可能表明对这种病原体的治疗方法进行了新的治疗方法。 公共卫生相关性：白色念珠菌是一种真菌病原体，会引起各种各样的机会感染，尤其是在住院的患者人群中，其造成了明显的发病率和死亡率。了解这种病原体与免疫系统的相互作用并逃避如何相互作用将有助于我们确定新的治疗靶标，以治疗真菌感染，因此与公共卫生直接相关。我们的研究将重点介绍胞质模式识别受体NLRP3如何被白色念珠菌激活，以及这如何塑造宿主随后的免疫反应。另外，从提出的研究中获得的信息还将阐明其他真菌生物的发病机理。