Neisseria gonorrhoeae causes about 600,000 new infections each year in the United States, with health- care costs approaching 2 billion dollars/year. The costs and human suffering are amplified by the fact that concomitant gonococcal infections appear to facilitate HIV transmission. Gonococci preferentially infect the human urogenital tract, and its ability to enter and transcytose this mucosal surface is a chief cause of pelvic inflammatory disease, tubal infertility, ectopic pregnancy, and chronic pelvic pain. Various surface components, i.e. lipooligosaccharide (LOS) and opacity proteins (Opa) are important in mediating these diseases. Most studies have used tissue culture models to study the role of individual surface components in the pathogenic process, even though it is likely that multiple components are needed and/or are able to act synergistically. The fact that this pathogen manipulates its outer membrane suggests that such modifications are important in pathogenesis. Nothing is known about possible interactions between the surface molecules, because to date, we have lacked bacterial strains that have invariant, defined surfaces. This has prevented us from developing a comprehensive understanding of the pathogenesis of gonococcal disease. The objectives of this proposal are to understand how Opa and LOS function in disease, and determine if these two antigens interact in the pathogenic process. The central hypothesis of the proposed research is that different variants of these surface antigens are important for the various stages of infection. We intend to test our hypotheses by pursuing three specific aims: We will determine how various surface structures promote invasion into different tissue culture cells, we will identify the signaling pathways activated by this interaction, and we will define the cellular responses in host cells that are initiated by gonococcal adherence. The results of our study will allow us to define how LOS and Opa variation contribute to disease pathogenesis. The impact on human health is expected to be significant, because the new knowledge will likely make possible new approaches to the prevention and treatment of gonorrhea. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI068888-02
Application #
7385979
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Hiltke, Thomas J
Project Start
2007-04-01
Project End
2011-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
2
Fiscal Year
2008
Total Cost
$327,777
Indirect Cost
Name
University of Maryland College Park
Department
Anatomy/Cell Biology
Type
Schools of Earth Sciences/Natur
DUNS #
790934285
City
College Park
State
MD
Country
United States
Zip Code
20742
Bhoopalan, Senthil V; Piekarowicz, Andrzej; Lenz, Jonathan D et al. (2016) nagZ Triggers Gonococcal Biofilm Disassembly. Sci Rep 6:22372
Stein, Daniel C; LeVan, Adriana; Hardy, Britney et al. (2015) Expression of Opacity Proteins Interferes with the Transmigration of Neisseria gonorrhoeae across Polarized Epithelial Cells. PLoS One 10:e0134342
Edwards, Vonetta L; Wang, Liang-Chun; Dawson, Valerie et al. (2013) Neisseria gonorrhoeae breaches the apical junction of polarized epithelial cells for transmigration by activating EGFR. Cell Microbiol 15:1042-57
LeVan, Adriana; Zimmerman, Lindsey I; Mahle, Amanda C et al. (2012) Construction and characterization of a derivative of Neisseria gonorrhoeae strain MS11 devoid of all opa genes. J Bacteriol 194:6468-78
Swanson, Karen V; Griffiss, J McLeod; Edwards, Vonetta L et al. (2011) Neisseria gonorrhoeae-induced transactivation of EGFR enhances gonococcal invasion. Cell Microbiol 13:1078-90
Song, Wenxia; Condron, Sara; Mocca, Brian T et al. (2008) Local and humoral immune responses against primary and repeat Neisseria gonorrhoeae genital tract infections of 17beta-estradiol-treated mice. Vaccine 26:5741-51
Bish, Samuel E; Song, Wenxia; Stein, Daniel C (2008) Quantification of bacterial internalization by host cells using a beta-lactamase reporter strain: Neisseria gonorrhoeae invasion into cervical epithelial cells requires bacterial viability. Microbes Infect 10:1182-91