The pathobiology of Neisseria gonorrhoeae lower female genital tract infection

Review Article published: 10 May 2011 doi: 10.3389/fmicb.2011.00102 The pathobiology of Neisseria gonorrhoeae lower female genital tract infection Jennifer L. Edwards1,2* and Emily K. Butler1 1 2 The Center for Microbial Pathogenesis, The Research Institute at Nationwide Children’s Hospital, The Ohio State University, Columbus, OH, USA The Department of Pediatrics, The Ohio State University, Columbus, OH, USA Edited by: Cynthia N. Cornelissen, Virginia Commonwealth University School of Medicine, USA Reviewed by: Margaret E. Bauer, Indiana University School of Medicine, USA Daoguo Zhou, Purdue University, USA *Correspondence: Jennifer L. Edwards, The Research Institute at Nationwide Children’s Hospital, 700 Children’s Drive, W503, Columbus, OH 43205, USA. e-mail: Infection and disease associated with Neisseria gonorrhoeae, the gonococcus, continue to be a global health problem. Asymptomatic and subclinical gonococcal infections occur at a high frequency in females; thus, the true incidence of N. gonorrhoeae infections are presumed to be severely underestimated. Inherent to this asymptomatic/subclinical diseased state is the continued prevalence of this organism within the general population, as well as the medical, economic, and social burden equated with the observed chronic, disease sequelae. As infections of the lower female genital tract (i.e., the uterine cervix) commonly result in subclinical disease, it follows that the pathobiology of cervical gonorrhea would differ from that observed for other sites of infection. In this regard, the potential responses to infection that are generated by the female reproductive tract mucosa are unique in that they are governed, in part, by cyclic fluctuations in steroid hormone levels. The lower female genital tract has the further distinction of being able to functionally discriminate between resident commensal microbiota and transient pathogens. The expression of functionally active complement receptor 3 by the lower, but not the upper, female genital tract mucosa; together with data indicating that gonococcal adherence to and invasion of primary cervical epithelial cells and tissue are predominately aided by this surfaceexpressed host molecule; provide one explanation for asymptomatic/subclinical gonococcal cervicitis. However, co-evolution of the gonococcus with its sole human host has endowed this organism with variable survival strategies that not only aid these bacteria in successfully evasion of immune detection and function but also enhance cervical colonization and cellular invasion. To this end, we herein summarize current knowledge pertaining to the pathobiology of gonococcal infection of the human cervix. Keywords: Neisseria gonorrhoeae, complement receptor 3, phospholipase, Akt, nitric oxide, uterine cervix, bacterial adherence and invasion, integrin signaling Introduction Health complications resulting from Neisseria gonorrhoeae (the gonococcus) disease occur mainly in women and are largely attributed to the predominately asymptomatic nature of lower genital tract, i.e., cervical, infection. Untreated, subclinical infection of the cervix can lead to upper genital tract involvement (e.g., salpingitis) and, potentially, to infertility. Consistent with the different clinical manifestations of disease observed between males (mostly acutely symptomatic) and females, the gonococcus uses variable mechanisms of pathogenesis that are dependent upon the host target cell, the specific microenvironment encountered within its (sole) human host, as well as strain-specific differences prevalent among N. gonorrhoeae strains. These include a repertoire of mechanisms to evade the host immune response and antimicrobial agents, to detoxify reactive oxidants, and to acquire iron during residence of the human host. The gonococcus predominately infects and colonizes the mucosal epithelium of the human urogenital tract. Although gonococcal vaginitis develops in female children in which menarche has not yet occurred, keratinization occurring with menarche prevents gonococcal vaginitis in the adult female. Thus, after the onset of menarche, the clinical presentation of gonococcal disease is not www.frontiersin.org varied. Gonococcal cervicitis results from urogenital gonococcal infection in females. Historically, conflicting models of gonococcal cervicitis have existed. Recent years have brought a resurgent interest in elucidating the molecular/cellular mechanisms contributing to cervical infection and its colonization, as well as in new technologies and model systems by which to examine many unanswered questions. It is now appreciated that not only are both the ecto- and the endocervix permissive for gonococcal infection/colonization but also that the gonococcus can no longer be considered a strictly extracellular pathogen (Evans, 1977; Edwards et al., 2001). Although various models are commonly used to study N. gonorrhoeae disease, this pathobiology cannot be completely mirrored using any single model system. Each model is limited in its utility when attempting to extrapolate these data to infection and disease in vivo. For example: (1) Human-specific constituents implicated in gonococcal pathogenesis are lacking in animal models; (2) molecular and cellular expression patterns, as well as functional responses, become altered during the immortalization/malignancy of cells lines; (3) primary cells and organ culture do not incorporate exogenous host factors; and (4) only a fixed, often undefined, window or duration of infection may be represented by clinical (naturally acquired/infected human tissues and fluids) specimens. Further, May 2011 | Volume 2 | Article 102 | 1 Edwards and Butler although studies have been performed using human volunteers, the asymptomatic nature of gonococcal cervicitis together with the risk for chronic disease sequelae in women, ethically restricts studies to males, and these investigations are limited to only those processes occurring early during the infection process as antibiotic therapy is given immediately with the onset of disease symptoms. The present manuscript is not a global review of gonococcal pathogenesis; rather, data derived from the use of cervical cell models are reviewed in an effort to highlight those events potentially contributing to cervical infection and disease in vivo. Several comprehensive reviews of N. gonorrhoeae pathogenesis are published (Woods and McGee, 1986; Ram et al., 1999; Dehio et al., 2000; Kline et al., 2003; Edwards and Apicella, 2004; Hamilton and Dillard, 2006; Seib et al., 2006; Steichen et al., 2008; Virji, 2009; Sadarangani et al., 2010; Srikhanta et al., 2010). The reader is also directed to the accompanying papers comprising this current, N. gonorrhoeae-focused, volume of Frontiers in Cellular and Immunity Microbiology for more information. Surface structures mediating adherence Included among the better-studied neisserial adhesins are: (1) porin, the (...truncated)