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Peptidoglycan metabolism and fragment release

肽聚糖代谢和片段释放

基本信息

批准号：
10053308
负责人：
Joseph P Dillard
金额：
$ 55.53万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2022-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10053308
关键词：
Adhesions Affect Agonist Amino Acids Bacteria Biochemical Bordetella pertussis Carboxypeptidase Cause of Death Cell Death Cell Separation Cell Wall Cells Characteristics Cicatrix Cytoplasm Cytotoxin Disaccharides Enzymes Epithelial Cells Generations Genes Glycosides Gonorrhea Gram-Negative Bacteria Growth Human IL8 gene Immune response Infection Inflammation Inflammatory Inflammatory Response Inflammatory Response Pathway Link Location Lytic Mammalian Oviducts Metabolism Methods Modeling Modification Molecular Muramidase Mutation Neisseria Neisseria gonorrhoeae Neisseria meningitidis Organism Pathogenicity Patients Pattern recognition receptor Pelvic Inflammatory Disease Peptides Peptidoglycan Process Production Proteins Proteomics Recycling Role System Tissues Trachea Virulence Factors Work cell injury cell type chronic pelvic pain cytokine dimer egg human tissue mutant neutrophil peptidoglycan monomer peptidoglycan receptor periplasm permease response transcriptomics tubal infertility uptake

项目摘要

As bacteria grow and divide, they constantly break down peptidoglycan strands to allow for cell wall expansion or reshaping the cell wall for septation and cell separation. Unlike most Gram-negative bacteria, Neisseria gonorrhoeae releases significant amounts of the peptidoglycan fragments produced during these processes. The released peptidoglycan fragments induce inflammatory responses in multiple cell types and cause sloughing of ciliated cells in the Fallopian tube. The ciliated cell sloughing is characteristic of gonococcal pelvic inflammatory disease and leads to the loss of the ability to move an egg down the oviduct. We have worked to characterize the enzymes that act in peptidoglycan breakdown so that we can understand the process of peptidoglycan fragment production. We are characterizing these enzymes to determine their substrates and products as well as subcellular localization and location relative to the septum on the gonococcal cell. Using mutants lacking genes for certain peptidoglycan degradation enzymes, we determined that ciliated cell sloughing occurs in response to peptidoglycan monomers with a three amino acid peptide, implicating pattern-recognition receptor NOD1 in the cellular response. We also discovered that gonococci release a second immunostimulatory muropeptide, a glycosidically-linked peptidoglycan dimer that stimulates NOD2. In this study we will characterize lytic transglycosylases for the generation of the peptidoglycan dimers and characterize the enzymes that create the free peptide that serves as a NOD1 agonist. We will examine AmpG function in peptidoglycan fragment recycling and determine how gonococci sense peptidoglycan fragments in the cytoplasm and regulate peptidoglycan fragment release or uptake. Finally we will characterize cellular responses to released peptidoglycan fragments to understand how Fallopian tube tissue is damaged in pelvic inflammatory disease and how neutrophils respond to released eptidoglycan fragments.

随着细菌的生长和分裂，它们不断地分解肽聚糖链，以允许细胞壁扩张或重塑细胞壁，以进行分裂和细胞分离。与大多数革兰氏阴性菌不同，淋病奈瑟菌释放出在这些过程中产生的大量肽聚糖片段。释放的肽聚糖片段在多种细胞类型中诱导炎症反应，并导致输卵管纤毛细胞脱落。纤毛细胞脱落是淋球菌性盆腔炎的特征，并导致卵子沿输卵管向下移动的能力丧失。我们已经研究了在肽聚糖分解中起作用的酶的特征，以便我们能够了解肽聚糖片段产生的过程。我们正在对这些酶进行表征，以确定它们的底物和产物，以及相对于淋球菌细胞隔膜的亚细胞定位和位置。利用缺乏某些肽聚糖降解酶基因的突变体，我们确定纤毛细胞在对具有三个氨基酸肽的肽聚糖单体的反应中发生脱落，暗示模式识别受体NOD1参与细胞反应。我们还发现淋球菌释放第二种免疫刺激多肽，一种糖苷连接的肽聚糖二聚体，刺激NOD2。在这项研究中，我们将表征用于生成肽聚糖二聚体的裂解转糖基酶，并表征产生作为NOD1激动剂的游离肽的酶。我们将研究AmpG在肽聚糖片段循环中的功能，并确定淋球菌如何在细胞质中感知肽聚糖片段并调节肽聚糖片段的释放或摄取。最后，我们将描述细胞对释放的肽聚糖片段的反应，以了解盆腔炎中输卵管组织是如何受损的，以及中性粒细胞如何对释放的肽聚糖片段作出反应。