Peptidoglycan metabolism and fragment release

University Of Wisconsin-Madison, Madison WI

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Abstract

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.