Clinical data indicate that there is a hormonal component to gonococcal infection in women;however, the effect of steroid hormones and oxygen limitation to gonococcal infection is an under-investigated, important, area of study. Our long-term goal is to elucidate the dynamic interactions, occurring between the gonococcus and the cervical epithelium, which contribute to asymptomatic disease in women, with the ultimate goal of improved women's health. The intent of this application is to provide a detailed understanding of how gonococci respond to steroid hormones, as well as to oxygen limitation (hypoxia), as would occur, in vivo, within the cervical microenvironment during gonococcal infection. It is our central hypothesis that, in vivo, gonococcal cervicitis is governed by oxygen limitation as well as by hormone-induced changes to the gonococcus and to the cervical epithelium. Asymptomatic cervicitis is the primary factor contributing to the propensity of women to develop chronic gonococcal disease sequelae, which translates into substantial associated health cost. Therefore, the rationale for the proposed studies is that a greater understanding of gonococcal pathogenesis in the context of the menses cycle is imperative to the future development of therapeutic strategies to combat gonococcal disease and to provide the framework for improved women's health. Thus, the proposed research is directly applicable to that part of the NIH's mission that pertains to the development of fundamental knowledge that will reduce the burden of human illness. Guided by strong preliminary data, two specific aims will be pursued to test this hypothesis: 1) Define changes occurring during cervical infection in the N. gonorrhoeae expression profile in response to steroid hormones and oxygen limitation;and 2) Define the effect of steroid hormones and oxygen limitation on the complement-gonococcus interaction in a primary human cervical epithelial cell model. Within Aim 1, we will identify gonococal constituents that are likely to contribute to gonococcal disease in vivo. A subset of these molecules will be analyzed further to define their potential contribution to promoting cervical disease. Complement production is responsive to steroid hormones and plays a critical role in mediating cervical infection. Thereby, Aim 2 comprises analyses to further define the complement-gonococcus interaction under conditions likely to be encountered in vivo. We will also characterize a putative gonococcal complement binding protein, NGO0033. A variety of cellular, molecular, and biochemical techniques will be used to complete the objectives of our Specific Aims. These investigations are the first to examine how combined, variable, physiological levels of steroid hormones and hypoxia potentially modulate bacterial pathogenesis by using a primary, human, epithelial cell model, and, thus, are innovative. The proposed research is significant because it is expected to generate exceedingly meaningful data regarding how gonococci respond to exogenous stresses (i. e. hormones, complement, and/or oxygen limitation) in the context of mucosal epithelial infection.
Women are more prone to develop chronic, often severe, consequences as a result of cervical infection with Neisseria gonorrhoeae, the bacterium that causes gonorrhea. The focus of this application is to define the effect of steroid hormones and oxygen limitation to gonococcal disease. The proposed studies are an important and under-investigated area of bacterial pathogenesis and are applicable to human health.
|Edwards, Jennifer L; Jennings, Michael P; Apicella, Michael A et al. (2016) Is gonococcal disease preventable? The importance of understanding immunity and pathogenesis in vaccine development. Crit Rev Microbiol 42:928-41|
|Craig, Andrew P; Gray, Richard T; Edwards, Jennifer L et al. (2015) The potential impact of vaccination on the prevalence of gonorrhea. Vaccine 33:4520-5|
|Atack, John M; Ibranovic, Ines; Ong, Cheryl-Lynn Y et al. (2014) A role for lactate dehydrogenases in the survival of Neisseria gonorrhoeae in human polymorphonuclear leukocytes and cervical epithelial cells. J Infect Dis 210:1311-8|
|Jen, Freda E-C; Warren, Matthew J; Schulz, Benjamin L et al. (2013) Dual pili post-translational modifications synergize to mediate meningococcal adherence to platelet activating factor receptor on human airway cells. PLoS Pathog 9:e1003377|
|Atack, John M; Srikhanta, Yogitha N; Djoko, Karrera Y et al. (2013) Characterization of an ntrX mutant of Neisseria gonorrhoeae reveals a response regulator that controls expression of respiratory enzymes in oxidase-positive proteobacteria. J Bacteriol 195:2632-41|
|Djoko, Karrera Y; Franiek, Jessica A; Edwards, Jennifer L et al. (2012) Phenotypic characterization of a copA mutant of Neisseria gonorrhoeae identifies a link between copper and nitrosative stress. Infect Immun 80:1065-71|
|Jennings, Michael P; Jen, Freda E-C; Roddam, Louise F et al. (2011) Neisseria gonorrhoeae pilin glycan contributes to CR3 activation during challenge of primary cervical epithelial cells. Cell Microbiol 13:885-96|
|Edwards, Jennifer L; Butler, Emily K (2011) The Pathobiology of Neisseria gonorrhoeae Lower Female Genital Tract Infection. Front Microbiol 2:102|
|Edwards, Jennifer L (2010) Neisseria gonorrhoeae survival during primary human cervical epithelial cell infection requires nitric oxide and is augmented by progesterone. Infect Immun 78:1202-13|
|Wu, Hsing-Ju; Seib, Kate L; Srikhanta, Yogitha N et al. (2010) Manganese regulation of virulence factors and oxidative stress resistance in Neisseria gonorrhoeae. J Proteomics 73:899-916|