Peptidoglycan metabolism and fragment release

肽聚糖代谢和片段释放

• 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
• 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

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（由申请方提供）：细菌生长和分裂需要肽聚糖细胞壁的持续降解和重组。这个过程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，通常会诱导炎症反应。在由淋病奈瑟氏菌、百日咳博德特氏菌或福氏志贺菌引起的感染中，肽聚糖片段被认为诱导大的炎症反应，其加重疾病或在很大程度上导致疾病期间发生的细胞损伤。在淋球菌性盆腔炎的器官培养模型中，这些肽聚糖片段重现了患有该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，毒性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的方式加工肽聚糖来影响宿主反应，从而导致通过不同途径的检测和信号传导。在N.释放的肽聚糖片段的组成与构成细胞壁的肽聚糖片段的组成不同，这表明细菌可以特异性地处理来自细胞壁降解的肽聚糖片段，以产生改变或影响宿主细胞过程的特异性产物。在这些研究中，我们将确定酶的重要生产和释放有毒肽聚糖片段的N。淋病，表征这些酶的功能，产生酶功能缺陷的突变体，从而产生毒性片段缺陷的突变体，并确定不同释放的肽聚糖片段在原发性人嗜中性粒细胞和输卵管组织的淋球菌感染中的作用。 公共卫生相关性：肽聚糖片段引起炎症反应，加重几种细菌感染的疾病。这些研究将确定这些毒力因子在细菌病原体淋球菌中产生的机制，并产生突变体，这些突变体将用于确定这些肽聚糖片段引起这种破坏性反应的分子机制。