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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI097157-03
Application #
8646868
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Hiltke, Thomas J
Project Start
2012-05-01
Project End
2017-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
3
Fiscal Year
2014
Total Cost
$540,613
Indirect Cost
$163,114
Name
University of Wisconsin Madison
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Woodhams, Katelynn L; Chan, Jia Mun; Lenz, Jonathan D et al. (2013) Peptidoglycan fragment release from Neisseria meningitidis. Infect Immun 81:3490-8