Peptidoglycan metabolism and fragment release

描述（由申请人提供）：细菌生长和分裂需要不断降解和重组肽聚糖细胞壁。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。在由淋病奈瑟菌、百日咳博德氏菌或福氏贺氏菌引起的感染中，肽聚糖片段被认为诱发了严重的炎症反应，从而加剧了疾病，或在很大程度上导致了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，这些肽聚糖片段概括了患有该疾病的妇女的组织损伤。毒性肽聚糖片段产生和随后释放的机制尚不清楚释放这些片段的任何细菌。此外，细菌可以通过不同的方式加工肽聚糖来影响宿主的反应，从而通过不同的途径进行检测和信号传递。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，我们将确定对淋病奈瑟菌产生和释放有毒肽聚糖片段至关重要的酶，表征这些酶的功能，产生酶功能缺陷从而导致毒性片段产生缺陷的突变体，并确定不同释放的肽聚糖片段在淋病球菌感染人初级中性粒细胞和输卵管组织中的作用。

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.