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

基本信息

批准号：
8037708
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
项目类别：
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/8037708
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&apos 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

项目摘要

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共生真菌，高度适应在宿主表面（例如粘膜组织）上生存，在粘膜组织中它无症状地定植于上皮表面。白色念珠菌还可引起严重的机会性感染，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。即使有最佳的医疗护理，与侵袭性真菌病相关的死亡率和发病率仍然很高。为了开发针对真菌病原体的新治疗方式，需要详细了解控制白色念珠菌等病原体所涉及的先天性和适应性免疫途径。在本提案中，我们将研究富含亮氨酸重复序列的核苷酸结合域受体 (NLR) 家族成员 Nlrp3 在识别和响应白色念珠菌感染中的作用。在巨噬细胞中，Nlrp3 在一种称为炎症小体的多蛋白复合物中被激活，以响应多种刺激。 Nlrp3 炎症小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，导致白细胞介素 (IL)-12 的释放。 Nlrp3 缺陷小鼠还表现出体内对白色念珠菌感染的易感性增加。该提案概述了三个新目标，即研究白色念珠菌激活 Nlrp3 所涉及的分子机制。在目标 1 中，响应于白色念珠菌的 Nlrp3 炎性体激活所需的初始启动步骤将通过确定 Nlrp3 炎性体激活是否需要通过 Syk/Card9 介导的信号传导来解决。在目标 2 中，我们将利用基因靶向小鼠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 炎性体激活中发挥作用。我们还将鉴定在酵母-菌丝转变过程中表达的念珠菌特异性因子，这些因子可被 Nlrp3 炎症小体直接感知。在目标 3 中，我们将研究 Nlrp3 炎性体在白色念珠菌体内感染后如何塑造随后的适应性免疫反应，特别是产生 IL-17 的 Th17 细胞的发育是否依赖于 Nlrp3 的存在。成功完成拟议的研究将提供对白色念珠菌如何激活 Nlrp3 炎性体的分子理解，并将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，这些研究对白色念珠菌发病机制的新见解可能会提出对抗这种病原体的新治疗方法。公共卫生相关性：白色念珠菌是一种真菌病原体，可引起多种机会性感染，特别是在住院患者群体中，其导致严重的发病率和死亡率。了解这种病原体如何与免疫系统相互作用并逃避免疫系统将有助于我们确定治疗真菌感染的新治疗靶点，因此与公共卫生直接相关。我们的研究将集中于白色念珠菌如何激活胞质模式识别受体 Nlrp3 以及它如何影响宿主随后的免疫反应。此外，从拟议研究中获得的信息还将揭示其他真菌生物的发病机制。