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Cannon, unpublished data. This suggests that the role of Opa proteins in promoting gonococcal urethritis in men resides in their ability to facilitate a gonococcus-PMN interaction.
A single, primary receptor that uniquely modulates the interaction of the gonococcus with PMNs has not been identified; however, this association occurs independently of CR3 It is also possible that one particular receptor mediates the PMN-gonococcus association under one set of environmental conditions e. 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. CEACAMs can serve as coreceptors for other cell surface receptors e.
Engagement of CEACAM sends a priming signal within PMNs that activates adhesion receptors without triggering a respiratory burst or the release of inflammatory mediators Therefore, an Opa-CEACAM interaction could potentially enhance gonococcal survival within these cells.
Opa proteins also promote intracellular survival by sequestering pyruvate kinase as a means to acquire pyruvate , which is required for gonococcal viability. CEACAMs are human-specific molecules and as such are not expressed by mice. Schmitter et al. It is currently not know if this interaction with CEACAM3 is mediated by a particular subset of those Opa proteins demonstrated to bind CEACAM receptors 45 or if all CEACAM-binding Opa proteins are equally efficient in their ability to serve as ligands for CEACAM3 and to trigger oxidative responses by granulocytes.
Studies performed by using the human challenge model of gonococcal disease have demonstrated that the ability of gonococci to acquire iron e. The initial site of gonococcal colonization in men is the urethral epithelial cell Fig. Disease is thought to occur as a sequential process in which an initial interaction between the gonococcal pilus and the urethral epithelium occurs.
The receptor for gonococcal pilus has not been examined by using primary urethral epithelial cells, nor has a pilus-CD46 interaction been shown in male exudates; consequently, it is not clear whether CD46 serves as the pilus receptor within the male urethra. Pilus expression, however, is required for successful infection of the urethral epithelium. Analysis of primary male urethral epithelial cells demonstrates that the observed intimate association between the urethral epithelium and the gonococcus Fig.
Pedestal formation beneath the bacterium is also observed with microscopic analysis of exudates collected from men with naturally acquired gonococcal urethritis 5 , Evidence suggests that endocytosis ensues primarily because of actin-dependent 80 and clathrin-dependent 97 processes.
It is not known whether similar events occur with gonococcal internalization within urethral epithelial cells. Small proportions of infecting gonococci are also observed to enter primary urethral epithelial cells by a macropinocytic mechanism, although membrane ruffling is not observed The intracellular fate of the gonococcus within the urethral epithelium is currently unclear.
Adherence of the gonococcus to the ASGP-R is dependent upon the presence of a terminal lacto- N -neotetraose LNnT moiety on LOS This moiety mimics human paragloboside and provides one means by which the gonococcus escapes immune recognition. Additionally, the LNnT epitope can serve as a sialic acid acceptor. The importance of the LNnT moiety to gonococcal pathogenesis in men can be inferred from human experimental infection studies and from clinical data obtained from men with naturally acquired gonorrhea, which demonstrate that LNnT is selected for in vivo 33 , , One study demonstrates that gonococci bearing the LNnT moiety on their LOS exhibit enhanced infectivity in humans It is thought that serum resistance conferred by LOS sialylation allows a greater proportion of gonococci to survive the harsh microenvironment of the urethral lumen during disease , , Consequently, a lower infectious dose is required to establish disease because a greater proportion of the infection inoculum survive and proliferate.
Sialylation of gonococci occurs within the male urogenital tract 6 , , Sialylation of the LNnT epitope, in vitro, impairs the ability of gonococci to invade primary urethral epithelial cells 96 and epithelial cell lines , and to be phagocytosed by neutrophils , These data are supported by one study in which, in vivo, sialylation of gonococci also impaired the ability of these organisms to cause disease in human volunteers Gonococcal infectivity is restored with sialic acid removal by neuraminidase or, presumably, by the replication of gonococci within the lumen of the urethra in the absence of host-derived CMP- N -acetylneuraminic acid.
Neuraminidase , and the ASGP-R 98 are present on human sperm. Neuraminidase is also present on the surface of professional phagocytic cells 51 , which are, generally, abundant in the urethral lumen under conditions favoring progressive gonococcal disease.
Sialylated gonococci in proximity to any of these cells might then be expected to become desialylated through exogenous neuraminidase activity. It can be speculated that subsequent gonococcal adherence to the ASGP-R on sperm 98 would then, in turn, facilitate disease transmission. The majority of gonococci transmitted from men to their partners have sialylated LOS. However, the presence or the absence of sialic acid on LOS does not influence the interaction of the gonococcus with primary cervical epithelial cells It is interesting to speculate that within the lower female genital tract sialylated gonococci may become modified to enhance disease transmission to men.
That is, neuraminidases produced by the vaginal microflora can potentially remove sialic acid from sialylated gonococci. Cervical epithelia also produce neuraminidase; however, the specificity of this enzyme to cleave endogenous or exogenous substrates exhibits cyclic variability The level of sialic acid found within the microenvironment of the cervix also exhibits cyclic variation Analysis of cervical secretions obtained from normal i.
These clinical findings are consistent with the ability of the gonococcus to evade and subvert host immune function. Further support for this idea is found in the work of Hedges et al. In contrast, Fichorova et al. The release of inflammatory cytokines by the cervical epithelium in response to N. Within minutes of infection of primary cervical epithelial cells, complement protein C3b is deposited on the lipid A portion of gonococcal LOS 63 and is rapidly inactivated to iC3b 64 Fig.
These data are supported by the predominance of iC3b in comparison to C3b on the surface of clinically isolated gonococci , , The affinity of complement factor H fH for sialylated LOS and for porin of a PI. A isotype may augment C3b inactivation. However, in primary cervical cell culture, C3b inactivation occurs in a kinetically similar manner on gonococci of either a PI. B isotype and on sialylated gonococci or on gonococci that are not sialylated Thus, C3b inactivation could be augmented by the presence of an LOS within the gonococcal outer membrane, as opposed to the LPS prevalent among gram-negative bacteria.
The resemblance of gonococcal LOS to human paraglobosides and glycosphingolipids, some of which serve as precursors for cervical mucus synthesis and which, consequently, may not be recognized as a complement-activating surface within the microenvironment of the cervix , , , , may also augment C3b inactivation.
In addition to the factor I fI cofactor activity of fH, CD46 can function as a cofactor for fI. However, infection studies performed with primary cervical epithelial cell cultures suggest that CD46 is not required for C3b inactivation on gonococci at the level of the uterine cervix Analysis of clinical biopsies obtained from women with culture-documented gonococcal cervicitis and infection studies performed with primary human cervical epithelial cells indicate that CR3 serves as the primary receptor for N.
Binding of gonococcal pilus to the I domain of CR3 65 probably allows the gonococcus to overcome the electrostatic repulsion between its own cell surface and that of the cervical cell and may juxtapose the gonococcus at the cervical cell surface, where complement concentrations would be expected to allow efficient opsonization for the subsequent intimate adherence of iC3b and gonococcal porin to the I-domain. Binding of the gonococcus to CR3 requires the cooperative action of iC3b bound to the gonococcal surface in conjunction with gonococcal porin and pilus Opa proteins do not appear to be required for adherence to or invasion of primary cervical epithelial cells 65 , A signal transduction cascade that is dependent upon the activation of wortmannin-sensitive kinases i.
Gonococci are then internalized within macropinosomes 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. 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 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.
Upon infection of primary cervical epithelial cells, gonococci release a phospholipase D homolog that gains access to the cervical intracellular environment nonspecifically through macropinocytosis of gonococci Gonococcal phospholipase D NgPLD appears to promote infection of primary cervical epithelial cells in several ways.
Recent data indicate that this secreted gonococcal protein augments signaling events that trigger CR3 mobilization to the surface of primary cervical cells This would ensure gonococcal receptor availability and, consequently, efficient targeting to and association with the cervical cell surface. NgPLD also modulates cervical cell signal transduction events leading to membrane ruffling. Mutant gonococci that lack functional NgPLD activity do not elicit membrane ruffling, and they are impaired in their ability to associate with and to invade primary human cervical cells The specific mechanism s e.
As with invasion of male urethral epithelial cells, the intracellular fate of gonococci within the cervical epithelium is unclear. Ligand binding to the I-domain of CR3 does not invoke a proinflammatory response in professional phagocytic cells 16 , 36 , , , , , Consequently, although this is speculative, the ability of gonococci to subvert cervical cell signal transduction cascades and the complement system in such a manner to allow a cooperative mechanism of CR3-mediated adherence to and invasion of the cervical epithelium may also enhance its survival within the lower female genital tract.
Gonococcal invasion in the absence of a respiratory burst would be expected to increase the number of gonococci that survive intracellularly, while inactivation of the complement system would enhance gonococcal survival extracellularly.
Consequently, subversion of host cell signal transduction and the complement system by the gonococcus within the lower female genital tract may potentially allow this bacterium to attain a carrier-like state. In this regard, it of interest that menses is associated with an increased risk to women for PID and for disseminated infection C3 production by the cervical epithelium exhibits cyclic variability, and the highest levels of C3 are detected during menses , Additionally, a correlation can be made between the presence or the absence of Opa and the site of gonococcal isolation i.
The ability of gonococci to use heme, hemoglobin, and haptoglobin-hemoglobin is also postulated to be responsible for the increased risk observed for women to develop PID and disseminated disease during menses 31 , Analyses of gonococci clinically isolated from women support this idea in that there may be a correlation between the expression of the hemoglobin receptor by gonococci and the onset of the menses cycle 4. Ascent to the upper female genital tract might be facilitated through the ability of gonococci to exhibit twitching motility, in conjunction with hormonal changes which influence the expression of complement and molecules serving as gonococcal receptors within the female genital tract.
Microscopic analysis of tissue biopsies indicates that the expression of CR3 progressively decreases in an ascending manner from the ectocervix to the fallopian tubes Conversely, expression of the lutropin receptor LHr increases in an ascending manner from the endometrium to the fallopian tubes, and expression is up regulated at the time of menses 26 , , It is speculated that the LHr serves as a receptor for gonococcal invasion of endometrial and fallopian tube epithelia 43 , 82 , Human chorionic gonadotropin hCG , a natural ligand for LHr, can competitively inhibit the association of gonococci with FTOC and Hec1B cells, presumably by interfering with an LHr-gonococcus interaction 82 , These data suggest that gonococci possess a surface molecule that mimics hCG.
Recently, Spence et al. The LHr is also present on the human uterus, placenta, decidua, and fetal membranes Although this is speculative, a gonococcus-LHr interaction occurring on decidua and placental membranes could potentially result in severe complications of disease and may, in part, contribute to the increased risk of spontaneous abortion associated with N.
Gonococcal adherence to fallopian tube epithelia occurs selectively on nonciliated cells 82 , , ; however, it is the ciliated cells of the fallopian tube epithelia that are subsequently shed If left untreated, complete loss of ciliary action can occur. It is presumed that the loss of the ciliated cells within the fallopian tube provides the gonococcus access to subepithelial tissues. Access to subepithelial tissue is also speculated to be obtained with invasion of nonciliated cells, after which gonococci are transcytosed to the basal lateral surface of these cells and released In Hec1B cells, the gonococcal protein L12 mediates transcytosis to the basal lateral surface ; however, this has yet to be demonstrated in FTOC.
Sialylation of intracellular gonococci before their exocytosis might potentially prime these organisms for disseminated infection by the increased serum resistance observed with sialylation. It is also postulated that while gonococci appear to initiate upper genital tract infections, gonococcal colonization is short-lived with increasing anoxic environmental conditions associated with inflammation and the introduction of secondary, invasive, microorganisms 47 , 52 , , It is additionally suggested that with extended infections, gonococci may actually reside within the uterine cul-de-sac of the peritoneal cavity 47 , Several studies have indicated that the CP serves as the primary mechanism of complement-mediated killing of gonococci.
Disseminated gonococcal infection is associated predominately with gonococci that express PI. A 34 , Porin molecules of the PI. A, but not the PI. B, isotype bind fH at a site distinct from that observed for sialylated LOS Binding of fH favors alternative pathway complement inactivation and increases the serum resistance observed for PI.
A-expressing gonococci. Within the CP, C4-binding protein C4bp functions in a manner analogous to that of fH by serving as a cofactor for fI-mediated inactivation of C4b. Another mechanism gonococci have adapted to increase their survival within human serum is the ability of gonococci of a PI.
B isotype to bind C4bp Binding of C4bp is specific for gonococci that are not sialylated. Deposition of C4b occurs on the phosphoethanolamine substitution of LOS Porin is intimately associated with LOS within the outer membrane of gonococci.
Consequently, the juxtaposition of porin with LOS may facilitate CP inactivation by mediating the interaction of either fH or C4bp with C4b. Crucial to the bactericidal action of the complement system is the assembly of a functional membrane attack complex MAC. Studies performed by Joiner and coworkers demonstrate that the serum resistance or sensitivity exhibited by a gonococcus is correlated with how MAC assembly occurs on the bacterium's surface, which they also show to occur in an aberrant manner on the surface of serum-resistant gonococci , The need for MAC involvement in controlling neisserial disease is further evidenced by the increased risk for neisserial infections associated with complement deficiencies Individuals deficient in terminal i.
In addition to the ability of sialylated LOS to bind fH to mediate increased serum resistance, the presence of sialic acid on LOS decreases C9 deposition upon the gonococcal surface Consequently, a functional MAC is not formed and gonococcus lysis cannot occur. Opa may also play a role in inhibiting MAC assembly on the surface of gonococci.
Increased serum resistance is observed among gonococci in the presence of heparin, which binds to Opa Although the mechanism by which serum resistance is conferred has not been elucidated, one possibility is that the binding of heparin to Opa augments the inhibitory effect of vitronectin on MAC assembly.
The gonococcus is exquisitely adapted to survival within its sole human host. It is uniquely capable of sensing and adapting to a particular host microenvironment. This is evident from the different mechanisms used by this bacterium to invade mucosal surfaces and to survive in the presence of human serum. Colonization of the male urethral epithelium is dependent upon the presence of transferrin or lactoferrin. Cytokine release contributes to the usually symptomatic nature of gonococcal disease in men and is accompanied by a large influx of PMNs, which in turn contribute to the observed cytokine release and inflammation.
The interaction of gonococci with PMNs is mediated by the interaction of two broad families of proteins, Opa gonococcal proteins and CEACAM host cell proteins. The specific interactions occurring between these two families of proteins may dictate specific host cellular responses and the survival or death of phagocytosed gonococci.
The PMN response to gonococci is further modulated by gonococcal porin, which inhibits PMN degranulation and the production and release of toxic oxidants from the host cell to the extracellular milieu. In this respect, porin may promote gonococcus survival, but gonococci possess multiple gene products that promote survival from varied host defense mechanisms.
In vitro studies and the ability to cultivate gonococci from patient exudates indicate that at least some gonococci survive the cytotoxic action of PMNs.
Gonococci are sialylated upon their LOS molecules while in residence within the PMN and must become desialylated before they are able to invade the urethral epithelial cell. Sialidases are present on human sperm, PMNs, and macrophages, and consequently, they could potentially desialylate proximal gonococci and thus contribute to disease progression. Transmission of gonococci to a sexual partner is aided, in part, by the ability of gonococci to bind to human sperm.
Within the lower female genital tract the presence or absence of sialic acid on the gonococcal surface does not appear to influence colonization, although sialidases present within the lower female gental tract may prime the gonococcus for transmission to the male urethra.
The interaction of gonococci with the uterine cervix is mediated by the cooperative actions of host and gonococcal constituents. Gonococcal pilus binds to CR3 present on the ectocervix and endocervix, positioning the bacterium at the cervical cell surface where complement is produced and activated.
C3b is inactivated to form iC3b; these processes are probably mediated by the affinity of porin for factor H of the alternative pathway and the proximity of porin to LOS in the gonococcal outer membrane. Engagement of CR3 triggers gonococcal internalization within macropinosomes.
Secreted gonococcal proteins, which ensure CR3 recruitment to the cervical cell surface, mediate these processes. Ascension to the upper female genital tract is mediated by both host and gonococcal factors that are subject to cyclic environmental changes occurring within the female genital tract. The LHr present on the endometrial and fallopian tube epithelia mediates the interaction of gonococci with the upper female genital tract. The ribosomal protein L12 serves as the gonococcal ligand mediating LHr adherence.
The association of the gonococcus with fallopian tube epithelia is limited to the nonciliated cells; however, ciliated cells are lost because of the toxicity associated with LOS and peptidoglycan release. Nonciliated cells are invaded by the gonococcus, and gonococci are transcytosed to the basal lateral surface where they are released and gain access to the subepithelial tissues.
Access to subepithelial spaces provides a gateway by which disseminated gonococcal infection can occur. Within the bloodstream, the interaction of the gonococcus with the complement system becomes critical for bacterial eradication and is thought to be dependent upon classical pathway activity and the presence of efficacious antibody.
However, gonococci have adapted multiple mechanisms by which they are able to evade the lytic action of the complement system, including C4b inactivation and the formation of a nonfunctional MAC on their cell surface. The gonococcus is unique in that it appears to possess a seemingly endless repertoire of pathogenic mechanisms by which it efficiently colonizes discrete microenvironments found within its sole human host.
This review has attempted to incorporate some of our current knowledge into a working model of how disease and disease transmission might occur in vivo, and in doing so we have attempted to highlight the differences in gonococcal pathogenesis observed between infection in males and infection in females.
Whereas an intimate association occurs between the gonococcus and the male urethral epithelium, i. Infection of the male urethra and infection of the upper female genital tract are usually associated with an inflammatory response.
In contrast, a significant proportion of women with lower genital tract infections exhibit asymptomatic or subclinical disease. The intracellular fate of the gonococcus within any given cell type is currently unclear.
It will therefore be of interest to determine whether the signal transduction cascades triggered with host cell engagement and the intracellular fate of this bacterium are as varied as are the portals of entry that it uses to become intracellular. Future studies will undoubtedly further our understanding of this unique human pathogen and the mechanisms it uses to exploit its human host.
In view of the increasing prevalence of antibiotic-resistant strains of gonococci, it is hoped that these studies will lead to the development of new effective therapeutic agents for the treatment and prevention of gonorrhea.
In light of our current knowledge, it is doubtful that a single agent or vaccine candidate will prove efficacious in all disease settings; however, with continued study it may be possible to develop strategies that would confer protection to a particular subgroup of individuals or prevent colonization of a discrete microenvironment within a human host.
We thankfully acknowledge B. Evans, D. Orr, and D. Fortenberry for providing us with the clinical cervical biopsies and P.
Rice for male urethral exudates. We are grateful to the Departments of Urology and Obstetrics and Gynecology at the University of Iowa for allowing us to obtain urethral and cervical tissues used to seed the primary cell cultures used in these studies. We also express our gratitude to M. Ketterer, H.
Harvey, and J. Shao for their assistance in compiling the manuscript. National Center for Biotechnology Information , U. National Library of Medicine Rockville Pike , Bethesda MD , USA. NCBI Skip to main content Skip to navigation Resources How To About NCBI Accesskeys My NCBI Sign in to NCBI Sign Out. PMC US National Library of Medicine National Institutes of Health. Journal List Clin Microbiol Rev v.
Clin Microbiol Rev. PMCID: PMC Jennifer L. Edwards and Michael A. Edwards Department of Microbiology, The University of Iowa, Iowa City, Iowa Find articles by Jennifer L.
Michael A. Apicella Department of Microbiology, The University of Iowa, Iowa City, Iowa Find articles by Michael A. Author information Copyright and License information Disclaimer.
Department of Microbiology, The University of Iowa, Iowa City, Iowa. Mailing address: The University of Iowa, 51 Newton Rd. Phone: Fax: E-mail: ude. This article has been cited by other articles in PMC. Abstract The molecular mechanisms used by the gonococcus to initiate infection exhibit gender specificity.
Open in a separate window. INFECTION OF THE LOWER FEMALE GENITAL TRACT The majority of gonococci transmitted from men to their partners have sialylated LOS. Acknowledgments We thankfully acknowledge B. The work described in this paper was supported by NIAID grants AI and AI Aderem, A. Wright, S. Silverstein, and Z. Ligated complement receptors do not activate the arachidonic acid cascade in resident macrophages.
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Boulton, J. Pongoski, A. Cochrane, and S. Induction of HIV-1 long terminal repeat-mediated transcription by Neisseria gonorrhoeae. AIDS 17 : Chen, J. Bavoil, and V. Chen, T. CGM1a antigen of neutrophils, a receptor of gonococcal opacity proteins. USA 93 : Grunert, A. Medina-Marino, and E. Several carcinoembryonic antigens CD66 serve as receptors for gonococcal opacity proteins.
Swanson, J. Wilson, and R. Chow, A. Malkasian, J. Marshall, and L. The bacteriology of pelvic inflammatory disease. Cohen, M. Cannon, A. Jerse, L. Charniga, S. Isbey, and L. Human experimentation with Neisseria gonorrhoeae : rationale, methods, and implications for the biology of infection and vaccine development.
Cooper, M. McGraw, and M. Localization of gonococcal lipopolysaccharide and its relationship to toxic damage in human fallopian tube mucosa. Cornelissen, C. Kelley, M. Hobbs, J. Cannon, M. Cohen, and P. The transferrin receptor expressed by gonococcal strain FA is required for experimental infection of human male volunteers.
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Try out PMC Labs and tell us what you think. 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 Porinn, which promotes neutrophil influx and an inflammatory response.
Gonococci invade the nonciliated epithelia, and the ciliated cells Sachsen Ladies Forum subjected to WWww cytotoxic effects of tumor necrosis factor alpha induced by gonococcal peptidoglycan Www Sex Porin 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 Deutsche Pormos present in the lower female genital tract.
A model of gonococcal pathogenesis is presented in the context of the male and female human urogenital tracts. Neisseria gonorrhoeaethe gonococcus, is a gram-negative diplococcus which causes the sexually transmitted disease gonorrhea.
The highest incidence of disease and Porinn sequelae occurs in less Sexx developed countries; however, greater thancases are reported to the Centers for Disease Control and Poein in the United Seex each year Teenagers and young adults are at high risk for infection, which is unsettling in view of the increased risk associated with gonorrhea for infection with human immunodeficiency virus HIV type 1 The gonococcus-induced increase in the local expression of viral RNA, in conjunction with the acute inflammatory response generated with gonococcal disease and the subsequent loss of mucosal integrity, is associated with the increased susceptibility to HIV type 1 In addition, susceptibility to chronic Porun associated with N.
One in 10 women suffers from Sx 8of which N. Although the urethra and the uterine cervix serve as the initial sites for gonococcal infection in men and women, respectively, infections WWww the conjunctiva, pharynx, Gruppensex Geschichten Www Sex Porin mucosa are also reported.
Studies reveal that the gonococcus can enter human cellsbut only recently has it been shown that Wwww organism is intracellular during human infection 5. A repertoire of virulence factors have been identified and allow this bacterium to successfully adapt to variable microenvironments Www Sex Porin its sole human host. This human adaptability and the repeated phase and antigenic change displayed by Sexx gonococcus have hampered vaccine development. Porin expression is stable for any given strain of N.
B isotype. Porin is highly immunogenic However, porin is intimately associated with reduction-modifiable protein Rmp or P. III 212527, and with LOS in the outer gonococcal membrane.
Blocking antibodies to Rmp 68,and to LOS 68 impair an efficacious immune response developed against porin. Therefore, a functional immune response may be only minimally stimulated by gonococcal infection or by Porrin This paper is WWww a global review of neisserial pathogenesis but rather attempts to incorporate into a working model recent advances made in understanding the molecular factors involved in gonococcal infection and in disease progression and transmission.
It is hoped that assembling such a Porkn in the context of the human male and female uro genital tracts Fig. A to C Working model of gonococcal pathogenesis within Porim lower female genital tract. Alternative Marie Francoise Aime complement components are produced and released by the cervical epithelia A. Upon N. Gonococcal pilus binds to the I-domain of CR3 allowing the bacterium to overcome the electrostatic repulsion between its own cell surface Garten Gif 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 Wwq 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 Www Sex Porin 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. 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.
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. Clathrin is recruited to the site of ASGP-R, and gonococcus-ASGP-R complexes are internalized in clathrin-coated pits in Ww 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. 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. Reference to N. It was not until A. Boswell also described what might possibly be the consequence of asymptomatic infection in women, in that his wife, who reportedly never exhibited symptoms of gonococcal infection, lost four of her nine pregnancies Neisser described the causative agent of gonorrhea, N.
The advent of sulfonamide in and penicillin in antibiotic therapy for the treatment of N. In the early s this trend reversed with the onset of oral contraceptive methods, and N. In the late s, with the onset Porn the HIV epidemic and a coincident widespread use of barrier contraceptives, the incidence of gonococcal infection again declined A recent increase in all sexually Ssx diseases is currently observed globally, as is the emergence of antibiotic resistance among organisms causing these diseases 1925 Xxx Twins, Today the incidence of gonorrhea in the United States is greater than five times that observed in Europe, although comparable high-risk groups exist in both regions Additionally, the gonorrhea Pprin in Australia is currently the highest that it has been in 20 years Despite the historic Anale Latexhuren of Simpson Sex. Discernment Kostenlose Sex Abenteuer gonococcal pathogenesis is hindered by the lack of an animal model that closely mimics human disease and that can be efficiently used to study the pathology of N.
Although several animal models have been described for reviews, see references 10 and 11no Srx model exists that mirrors the full spectrum of disease caused by the gonococcus at any given site within the human body. Logic would dictate that the propensity of gonococci to undergo both phase and antigenic variation, in a seemingly random process, would be subject to variable selective environmental pressures dependent upon a chosen model system.
Therefore, in selecting a model system Www Sex Porin which to study gonococcal pathogenesis, it is Www Sex Porin to consider the specific question under study. The human male experimental challenge Proin 48 and the development of a primary human male urethral epithelial cell culture system 97 have greatly enhanced our knowledge of SSex specific factors involved in early events permitting N. These models do not evaluate cellular and molecular events occurring with sustained infection.
Additionally, clinical observations and data obtained from in vitro infection studies suggest that conclusions drawn from the study of these male infection models cannot be extrapolated Www Sex Porin pertain to infection in women.
The severity of adverse complications associated with N. Microscopic analyses of clinical biopsies 646769and of male urethral exudates 5 have provided some insight into successful gonococcal infection as it occurs in vivo, but these analyses are also not without caveats in that they are subject to personal observation and interpretation. Additionally, observations made cannot be correlated to pertain to any given time point postinfection. Primary cell and organ culture systems have also been developed to examine the gonococcal interaction within Potin lower and upper female genital tracts; however, these systems are site SSex, and, consequently, a global analysis of the female genital tract is not possible.
The female genital tract is composed of a heterogeneous mixture of epithelia, forming a complex microenvironment which is not easily replicated in vitro and which is subject to change concurrent with a woman's menses cycle.
Thus, it is possible that data obtained from primary cell and organ Wwww might provide only a small hint of gonococcal pathogenesis as it occurs in vivo at any site within the female genital tract. The development wWw a female mouse model of genital tract infection has served and Www Sex Porin continue to serve as a valuable tool by which to study gonococcal pathogenesis in an immunologically defined environment, However, it is currently not clear whether data obtained from the mouse model of female genital tract infection is reflective of infection as it occurs within the human female genital tract, because mice fail to express several human-specific receptors e.
Additionally, wWw levels of estrogen are required to establish infection in miceBig Bunny Download, and the contribution of increased estrogen to the data obtained is not known Cell lines Poron often altered in their protein and receptor expression patterns because of their immortal nature and continued laboratory maintenance 54Www Sex Porin76,,,,, Additionally, altered protein expression can result in additive or synergistic alternative functional responses within these immortal cells compared to their respective Porih tissues.
It is also noteworthy that some cell lines commonly Wqw to study gonococcal pathogenesis are of ambiguous or irrelevant with respect to natural Porno Runterladen origin. It is therefore difficult to extrapolate data obtained from the use of immortal cell lines to gonococcal infection at any specific site within the sole human host, and caution must be exercised when drawing conclusions from these studies because immortal cell lines may not be truly representative of the epithelia encountered by the gonococcus in vivo.
However, the use of immortal cells has greatly contributed to our Breast Expansion Software of both the human and the gonococcal constituents that might play a role Porrin potentiating disease in vivo. Gonococcal outer membrane constituents that are predominately thought to play a role in epithelial Wws colonization and invasion include pili, Opa, porin, and LOS.
Several groups Pori demonstrated that pili play a critical role in forming an initial attachment with host cells 282948, Through their ability to exhibit twitching motility, pili may also provide one mechanism by which nonmotile gonococci are able to colonize and to ascend mucosal surfaces The complement regulatory protein, CD46 or membrane cofactor receptoris a human-specific, transmembrane protein that is expressed by all nucleated cells.
In some cells, CD46 has been demonstrated to serve as a receptor for gonococcal pilus In a separate study Gina Wide the A epidermoid carcinoma cell Sxe, a pilus-induced calcium flux resulted in the exocytosis of host cell lysosomal contents, with some lysosome-associated membrane Potin 1 Lamp1 redistribution to the plasma membrane 12 Pilus engagement has also been demonstrated to play a role in host cell cytoskeletal rearrangements 90, Collectively, these data suggest that pili modulate host cell signaling mechanisms to aid gonococcal epithelial invasion.
Opa proteins are thought to contribute to the cellular trophisms exhibited by gonococci and are divided into two classes based on their ability to differentially recognize host cell surface molecules. Sexx classes Sx represented by Opa 50i. Vitronectin 616281 and fibronectin function as required bridging molecules between the gonococcus and its target HSPG wWw s.
In Chang conjunctiva epithelial cells, a direct Opa 50 -HSPG interaction has Poin demonstrated This interaction is thought to trigger a signal transduction cascade resulting in phosphatidylcholine-dependent phospholipase C-mediated generation of diacylglycerol These processes are speculated to modulate the cytoskeletal rearrangements required for endocytosis of the cell-associated gonococcus 84 CEACAMs exist as variable isoforms that are differentially expressed by a variety of different cell Poein.
Two isoforms, CEACAM1 or CD66a and CEACAM5 or CD66eare found on some epithelial cells. Although Opa proteins Wdw been demonstrated to colocalize with CEACAM in tissue culture cell lines 4586,CEACAM expression Porno Teen Lesbian altered in immortal cells,,and therefore an Opa-CEACAM interaction at the level of Rita Ora Porno mucosal epithelia may or may not actually occur in vivo.
However, Virji et al. Opa-CEACAM interactions have also been demonstrated on professional phagocytic cells 14487 Ses activation, in turn, triggers cytoskeletal rearrangement and internalization of the gonococcus