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Review
, 17 (4), 965-81, table of contents

The Molecular Mechanisms Used by Neisseria Gonorrhoeae to Initiate Infection Differ Between Men and Women

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Review

The Molecular Mechanisms Used by Neisseria Gonorrhoeae to Initiate Infection Differ Between Men and Women

Jennifer L Edwards et al. Clin Microbiol Rev.

Abstract

The molecular mechanisms used by the gonococcus to initiate infection exhibit gender specificity. The clinical presentations of disease are also strikingly different upon comparison of gonococcal urethritis to gonococcal cervicitis. An intimate association occurs between the gonococcus and the urethral epithelium and is mediated by the asialoglycoprotein receptor. Gonococcal interaction with the urethral epithelia cell triggers cytokine release, which promotes neutrophil influx and an inflammatory response. Similarly, gonococcal infection of the upper female genital tract also results in inflammation. Gonococci invade the nonciliated epithelia, and the ciliated cells are subjected to the cytotoxic effects of tumor necrosis factor alpha induced by gonococcal peptidoglycan and lipooligosaccharide. In contrast, gonococcal infection of the lower female genital tract is typically asymptomatic. This is in part the result of the ability of the gonococcus to subvert the alternative pathway of complement present in the lower female genital tract. Gonococcal engagement of complement receptor 3 on the cervical epithelia results in membrane ruffling and does not promote inflammation. A model of gonococcal pathogenesis is presented in the context of the male and female human urogenital tracts.

Figures

FIG. 1.
FIG. 1.
(A to C) Working model of gonococcal pathogenesis within the lower female genital tract. Alternative pathway complement components are produced and released by the cervical epithelia (A). Upon N. gonorrhoeae infection, complement is activated. Gonococcal pilus binds to the I-domain of CR3 allowing the bacterium to overcome the electrostatic repulsion between its own cell surface and that of the host cell. This places the gonococcus within proximity to the cervical cell surface where complement components would be sufficient to allow deposition upon the bacterial cell surface (B). C3b forms a covalent association with the lipid A core of gonococcal LOS and is rapidly inactivated to iC3b. The affinity of gonococcal porin for factor H may augment iC3b formation. The proximity of porin to LOS in the outer membrane may spatially favor the intimate association between iC3b and porin with the CR3 I-domain (C [inset]). Engagement of CR3 triggers a complex signal transduction cascade mediated by the Src-family tyrosine kinases and Rho GTPases (C). These processes result in vinculin- and ezrin-enriched focal complex formation and membrane ruffling, i.e., trigger mechanism of invasion. Secreted NgPLD modulates cervical cell signal transduction by playing a role in CR3 recruitment to the cervical cell surface and by modulating cytoskeletal reorganization. Additionally this protein augments intracellular survival of gonococci after their internalization within macropinosomes. Sialylated gonococci are eventually released from the cervical cell, where they are free to invade more of the cervical epithelia or where they become primed for transmission to the male urethra upon sialic acid removal by sialidases present within the female genital tract. (D) Invasion of the male urethral epithelium is mediated by an interaction between the terminal galactose moiety of LOS and the ASGP-R. (E) An intimate association occurs between the gonococcus and the urethral cell membrane, i.e., the zippering mechanism of invasion. Clathrin is recruited to the site of ASGP-R, and gonococcus-ASGP-R complexes are internalized in clathrin-coated pits in an actin-dependent process. Within the endosome a drop in pH is proposed to release the ASGP-R from the gonococcus surface, and clathrin molecules are lost. ASGP-R is recruited to the urethral cell surface, where it is available to serve as a receptor for more gonococci. (F) Engagement of the ASGP-R triggers cellular responses resulting in membrane pedestal formation beneath receptor-gonococcus complexes and activation of transcription factors required for the production of the inflammatory cytokines IL-6, IL-8, and TNF-α. Neutrophil influx accompanies cytokine release. Sialylated gonococci are eventually released from the urethral epithelium, where they can then be transmitted to a female partner. However, sialic acid on the gonococcus surface does not influence the ability of these organisms to associate with the uterine cervix.
FIG. 2.
FIG. 2.
Interaction of the gonococcus with male urethral epithelia. (A) Transmission electron micrograph of a urethral epithelial cell within a urethral exudate obtained from a male with naturally acquired gonococcal urethritis. Gonococci are indicated by arrows. (B) Scanning electron micrograph of primary male urethral epithelial cells after a 2-h infection. Notice the intimate association that occurs between the gonococcal and the host cell membranes in both panels. Magnifications, ×23,000 (A) and×40,000 (B).
FIG. 3.
FIG. 3.
Gonococci colocalize with CR3 in vivo. Clinical biopsies were obtained from women with culture-documented gonococcal cervicitis and immunoprocessed for confocal microscopy. CR3 present on the cervical cell surface is visible as green fluorescence, and gonococci are visible as red fluorescence. Colocalization of the gonococcus with CR3 occurs as yellow fluorescence because of the combined signal of the two fluorophores. Areas of colocalization are indicated by arrows. Magnification, ×40.
FIG. 4.
FIG. 4.
Scanning and transmission electron microscopy demonstrates that membrane ruffling occurs upon gonococcal cervical infection in vitro and in vivo. Membrane ruffling is observed after a 90-min infection of primary endocervical cells (A) and after a 2-h infection of primary ectocervical cells (B and D). A large membrane protrusion (small arrows) surrounds a gonococcus in a clinical biopsy obtained from a woman with culture-documented gonococcal cervicitis and is indicative of membrane ruffling (C). Additionally, this bacterium is found residing within a large spacious structure (large arrows), which is also suggestive of membrane ruffling (C). Panel D shows a high magnification of the gonococcus wrapped in the membrane ruffle shown in panel B. Gonococci are indicated by arrows in panels A, B, and D. Magnifications, ×11,000 (A), ×13,000 (B), ×40,000 (C), and ×45,000 (D).

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