Peptidoglycan metabolism and fragment release

肽聚糖代谢和片段释放

基本信息

批准号：
8369673
负责人：
Joseph P Dillard
金额：
$ 48.41万
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 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8369673
关键词：
Affect Alanine Amidohydrolases Antibodies Bacteria Bacterial Infections Biochemical Bordetella pertussis Carboxypeptidase Cause of Death Cell Separation Cell Wall Cell physiology Cells Cleaved cell Data Detection Disease Endopeptidases Enzyme Gene Enzymes Epithelial Gene Mutation Genes Genetic Transcription Gonorrhea Growth Human Immune response Infection Inflammatory Response Knock-out Knockout Mice Location Lytic Mammalian Oviducts Metabolism Modeling Molecular Mutate Mutation Neisseria gonorrhoeae Organ Culture Techniques Pathway interactions Pelvic Inflammatory Disease Peptide Hydrolases Peptides Peptidoglycan Play Process Production RNA Sequences Reaction Recycling Role Shigella flexneri Side Signal Transduction Squid System Testing Tissues Vibrio fischeri Virulence Factors Woman amidase biological systems cell injury cell type crosslink genetic manipulation migration mutant neutrophil pathogen peptidoglycan monomer receptor response

项目摘要

DESCRIPTION (provided by applicant): Bacterial growth and division requires constant degradation and reassembly of the peptidoglycan cell wall. This process generates small peptidoglycan fragments that can be released by the bacteria and sensed by host cells, often inducing an inflammatory response. In infections caused by Neisseria gonorrhoeae, Bordetella pertussis, or Shigella flexneri, peptidoglycan fragments are thought to induce a large inflammatory response that exacerbates disease or is largely responsible for the cell damage occurring during the disease. In the organ culture model of gonococcal pelvic inflammatory disease, these peptidoglycan fragments recapitulate the tissue damage seen in women with the disease. The mechanisms for toxic peptidoglycan fragment production and subsequent release are not known for any of the bacteria that release these fragments. Furthermore bacteria can affect the host response by processing the peptidoglycan in different ways, resulting in detection and signaling through different pathways. In N. gonorrhoeae the composition of released peptidoglycan fragments is different from that which makes up the cell wall, suggesting that the bacteria may specifically process peptidoglycan fragments from cell wall degradation to produce specific products that alter or effect host cell processes. In these studies we will identify enzymes important for the production and release of toxic peptidoglycan fragments by N. gonorrhoeae, characterize the function of these enzymes, produce mutants defective in enzyme function and thus defective in toxic fragment production, and determine the effects of different released peptidoglycan fragments in gonococcal infection of primary human neutrophils and Fallopian tube tissue. PUBLIC HEALTH RELEVANCE: Peptidoglycan fragments cause inflammatory responses that exacerbate disease in several bacterial infections. These studies will determine the mechanisms by which these virulence factors are created in the bacterial pathogen Neisseria gonorrhoeae and generate mutants that will be used to determine the molecular mechanisms by which such peptidoglycan fragments cause this destructive response.

描述（由申请人提供）：细菌生长和分裂需要肽聚糖细胞壁的不断降解和重新组装。这个过程会产生小的肽聚糖片段，这些片段可以被细菌释放并被宿主细胞感知，通常会引起炎症反应。在由淋病奈瑟氏球菌、百日咳博德特氏菌或福氏志贺氏菌引起的感染中，肽聚糖片段被认为会诱发大的炎症反应，从而加剧疾病或在疾病期间发生细胞损伤。在淋菌性盆腔炎的器官培养模型中，这些肽聚糖片段再现了患有该疾病的女性中所见的组织损伤。对于释放这些片段的任何细菌来说，有毒肽聚糖片段产生和随后释放的机制尚不清楚。此外，细菌可以通过以不同方式处理肽聚糖来影响宿主反应，从而通过不同途径进行检测和信号传导。在淋病奈瑟菌中，释放的肽聚糖片段的组成与构成细胞壁的组成不同，这表明细菌可能特异性地处理细胞壁降解产生的肽聚糖片段，以产生改变或影响宿主细胞过程的特定产物。在这些研究中，我们将鉴定对淋病奈瑟菌有毒肽聚糖片段的产生和释放很重要的酶，表征这些酶的功能，产生酶功能缺陷的突变体，从而导致有毒片段产生缺陷，并确定不同释放的肽聚糖片段的影响。原代人中性粒细胞和输卵管组织的淋球菌感染中的肽聚糖片段。公共卫生相关性：肽聚糖片段会引起炎症反应，从而加剧多种细菌感染的疾病。这些研究将确定在细菌病原体淋病奈瑟菌中产生这些毒力因子的机制，并产生突变体，这些突变体将用于确定此类肽聚糖片段引起这种破坏性反应的分子机制。