Peptidoglycan metabolism and fragment release

描述(申请人提供)：细菌的生长和分裂需要肽聚糖细胞壁的不断降解和重组。这一过程会产生细小的肽聚糖片段，这些片段可以被细菌释放并被宿主细胞感知，通常会引发炎症反应。在由淋球菌、百日咳杆菌或福氏志贺氏菌引起的感染中，肽多聚糖片段被认为能诱导大量炎症反应，从而加剧疾病，或者是疾病期间发生的细胞损伤的主要原因。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这种疾病的女性的组织损伤。对于任何释放这些片段的细菌来说，有毒的肽聚糖片段产生和随后释放的机制都是未知的。此外，细菌可以通过不同的方式处理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组成细胞壁的不同，这表明细菌可能专门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，我们将鉴定淋球菌产生和释放有毒肽聚糖片段的重要酶，鉴定这些酶的功能，产生酶功能缺陷从而产生有毒片段缺陷的突变株，并确定不同释放的肽聚糖片段在淋球菌感染原代人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.