Innate Immune Sensing of Bacterial Sugars

细菌糖的先天免疫感应

• 批准号: 8442856
• 负责人: David M. Underhill
• 金额: $ 31.85万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8442856
• 关键词: Acetylglucosamine; Acetylmuramyl-Alanyl-Isoglutamine; Amino Acids; Amoeba genus; Bacteria; Binding; Biochemical; Caspase-1; Cell Wall; Cells; Cellular biology; Cleaved cell; Complex; Cytosol; Dendritic Cells; Detection; Distant; Eating; Energy-Generating Resources; Enzymes; Fluorescence Microscopy; Genes; Germ Lines; Gram-Negative Bacteria; Heart Diseases; Homeostasis; Host Defense; Housekeeping; Immune; Immune response; Immune system; In Vitro; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interleukin-1; Interleukin-18; Knock-out; Knockout Mice; Ligands; Link; Lipopolysaccharides; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Methods; Microbe; Microscopy; Mitochondria; Myelogenous; N-Acetylglucosamine kinase; Natural Immunity; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Organism; Pathogenesis; Pathway interactions; Pattern recognition receptor; Peptides; Peptidoglycan; Phagocytes; Phagocytosis; Phagolysosome; Phagosomes; Process; Proteins; Recycling; Role; Signal Pathway; Signal Transduction; Staphylococcus aureus; Streptococcus pneumoniae; Stretching; Structure; Surface; System; TLR4 gene; Tissues; cell killing; computerized data processing; cytokine; detector; glucose metabolism; hexokinase; in vivo; killings; macrophage; microbial; pathogen; receptor; response; sugar

DESCRIPTION (provided by applicant): The innate immune system recognizes microbial pathogens using germ line encoded receptors which recognize conserved structures made by microbes. For example, the "pattern recognition receptor" TLR4 recognizes lipopolysaccharides produced as part of the cell walls of Gram-negative bacteria. When professional phagocytic cells such as macrophages and dendritic cells internalize and degrade microbes, structures may be released. For example, bacterial cell wall peptidoglycan may be cleaved to release muramyl dipeptide, a ligand for the cytosolic pattern recognition receptor Nod2. In this project, we will stretch the definition of a pattern recognition receptor to include the host enzyme hexokinase, a central enzyme in cellular glucose metabolism. We have shown that upon degradation of peptidoglycan in phagosomes a component sugar, N-acetylglucosamine, is freed up and transported into the cytosol where it interacts with hexokinase causing release of the enzyme from the mitochondrial surface. Hexokinase release from mitochondria initiates a signaling process culminating in activation of caspase-1 in an "inflammasome" complex which is responsible for processing and release of the key pro-inflammatory cytokines IL-1¿ and IL-18 (among other effects). Thus hexokinase is the "receptor" that detects the presence of this microbe-derived sugar. Endogenously produced N-acetylglucosamine is not normally found free in the cytosol and thus does not engage hexokinase. In this project we will characterize this innate immune mechanism further in three aims. In aim one we will characterize the cell biology of hexokinase signaling in macrophages and dendritic cells and determine how the process is regulated so as not to be toxic to the cells. In aim two we will define the role of the pathway in host defense through characterizing the function of the host enzyme N-acetylglucosamine kinase as a negative regulator in vitro and in vivo in knockout mice. In aim three well will explor how the Gram-positive peptidoglycan recycling system can be manipulated to influence signaling by this pathway in immune cells and alter microbial pathogenesis.

描述（由申请人提供）：先天免疫系统使用种系编码受体识别微生物病原体，所述受体识别微生物形成的保守结构。例如，“模式识别受体”TLR4 识别作为革兰氏阴性细菌细胞壁一部分产生的脂多糖。当巨噬细胞和树突状细胞等专业吞噬细胞内化并降解微生物时，结构可能会被释放。例如，细菌细胞壁肽聚糖可被裂解以释放胞壁酰二肽，胞质模式识别受体Nod2的配体。在这个项目中，我们将扩展模式识别受体的定义，以包括宿主酶己糖激酶，它是细胞葡萄糖代谢中的一种中心酶。我们已经证明，在吞噬体中肽聚糖降解后，一种成分糖，N-乙酰氨基葡萄糖，被释放并转运到胞质溶胶中，在胞质溶胶中它与己糖激酶相互作用，导致酶从线粒体表面释放。线粒体释放的己糖激酶启动信号传导过程，最终激活“炎性体”复合物中的 caspase-1，该复合物负责处理和释放关键的促炎细胞因子 IL-1¿ 和 IL-18（以及其他作用）。因此，己糖激酶是检测这种微生物来源的糖的存在的“受体”。内源产生的 N-乙酰氨基葡萄糖通常不会游离在细胞质中，因此不会与己糖激酶结合。在这个项目中，我们将通过三个目标进一步描述这种先天免疫机制。在目标一中，我们将描述巨噬细胞和树突状细胞中己糖激酶信号传导的细胞生物学特征，并确定如何调节该过程以免对细胞产生毒性。在目标二中，我们将通过表征宿主酶 N-乙酰氨基葡萄糖激酶作为敲除小鼠体外和体内负调节因子的功能来定义该途径在宿主防御中的作用。第三口井的目标是探索如何操纵革兰氏阳性肽聚糖回收系统来影响免疫细胞中该途径的信号传导并改变微生物发病机制。