权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mechanisms of peptidoglycan-induced modulation of metabolic and inflammatory responses to bacteria

肽聚糖诱导的细菌代谢和炎症反应调节机制

基本信息

批准号：
10356878
负责人：
Andrea Jean Wolf
金额：
$ 41.75万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-10 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10356878
关键词：
Adaptive Immune System Affect Amino Acids Antigen Presentation Bacillus Bacteria Bacterial Infections Bone Marrow CASP1 gene Cell Wall Cells Cellular Structures Complex Cytosol Dendritic Cells Dissociation Enzymes Exposure to Family Glycolysis Glycolysis Inhibition Gram-Positive Bacteria Gram-Positive Bacterial Infections Hexokinase 2 Host Defense Immune Immune response Immunologic Receptors Immunologic Surveillance Infection Inflammasome Inflammation Inflammatory Inflammatory Response Innate Immune Response Innate Immune System Interleukin-18 Knockout Mice Ligands Lipids Membrane Metabolic Metabolism Microbe Mitochondria Mus Myelogenous Myeloid Cells Outcome Outer Mitochondrial Membrane Pathology Pathway interactions Peptide Hydrolases Peptidoglycan Phagocytes Phagosomes Phenotype Play Polymers Process Production Proteins Regulation Research Resistance Role SLC2A1 gene Signal Transduction Small Interfering RNA Staphylococcus aureus Therapeutic Tissues Toll-like receptors Vertebral column adaptive immune response crosslink cytokine design experimental study hexokinase in vivo inflammatory milieu inhibitor knock-down macrophage mouse model receptor recruit response sugar

项目摘要

ABSTRACT Immune surveillance by phagocytic cells plays a vital role in controlling infections by internalize bacteria and kill them by a process of enzymatic degradation. Degradation also releases bacterial molecules that activate innate immune receptors and antigens for presentation to the adaptive immune system ultimately orchestrating the overall immune response to a microbe. The cell wall of gram-positive bacteria, like Staphylococcus aureus, is predominantly composed peptidoglycan, an amino acid-crosslinked sugar polymer. We recently demonstrated that the monomeric sugar, n-acetylglucosamine, released during peptidoglycan degradation, is inflammatory. N-acetylglucosamine interacts with the glycolytic enzyme hexokinase, inhibiting its function. As a consequence, hexokinase’s interaction with the mitochondrial outer membrane is disrupted and this dissociation initiates a signaling cascade responsible for assembly of the multi-protein NLRP3 inflammasome complex necessary for activation of the protease caspase-1. Caspase- 1 is responsible for the cleavage and activation of several key inflammatory cytokines, including IL-1b and IL-18, important for inflammatory cell recruitment and activation. Our results suggest that phagocytic cells have adapted their normal glycolytic regulation to sense abnormally high levels of a bacterial sugar as danger. To evade immune surveillance, bacteria modify their peptidoglycan layer to resist degradation by phagocytic cells and limiting the availability of innate inflammatory signals, including n-acetylglucosamine. The amount of n-acetylglucosamine impacting hexokinase function and glycolysis will depend on transport across the phagosomal membrane into the cytosol. Preliminary evidence suggests that the amount of IL- 1b produced by phagocytic cells, specifically in response to peptidoglycan, is dependent on the function of the GLUT family of sugar transports. In addition, we have generated a mouse model deficient for one of the three hexokinases expressed by phagocytic cells and observed differential impacts on glycolysis and inflammatory responses. This proposal aims to define the roles of the three hexokinases expressed by phagocytic cell in the inflammatory response to gram-positive bacteria peptidoglycan, as well characterize the transport and impact of peptidoglycan-derived n-acetylglucosamine on the metabolism and inflammatory responses of phagocytic cells. We hypothesize that the overall degree of inflammation induced by gram-positive bacteria is impacted by the amount and availability of n-acetylglucosamine generating during bacterial peptidoglycan degradation due in part to n-acetylglucosamine’s inhibition of glycolytic metabolism.

摘要