Chapter 11 : : Adaptation and Survival in the Urogenital Tract

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Uncomplicated gonorrhea is most commonly an acute urogenital infection involving the urethra in men and the endocervix in women of reproductive age. Upon entering the urogenital tract, adheres to columnar epithelial cells, a step that presumably enables the gonococcus to withstand the flushing force of urine and the constant shedding of cervical mucus. Transcriptional regulation of genes in response to environmental stimuli in the mucus layer may coordinate adaptation of this pathogen to nutritionally different microenvironments and to physiological stress induced by nonspecific host defenses. The major pilin subunit, PilE, is encoded by one or two expression loci () on the chromosome. This chapter focuses on the survival mechanisms utilized by the gonococcus specifically in the context of the urogenital mucosa. The isolation of a gonococcal mutant by Thomas and Sparling facilitated the identification of numerous -dependent iron-induced (Fip) and iron-repressed (Frp) proteins by two-dimensional electrophoresis; from this work one might predict the existence of gonococcal virulence genes that are regulated by iron but not involved in iron uptake. Insights from these studies have fostered theories regarding the functions of these molecules and the role of variable gene expression in gonococcal adaptation and transmission. The development of animal models for studying specific aspects of gonococcal infection in a female background should also be pursued, incorporating transgenic mice when possible to better mimic human infection.

Citation: Jerse A. 2000. : Adaptation and Survival in the Urogenital Tract, p 201-227. In Nataro J, Blaser M, Cunningham-Rundles S (ed), Persistent Bacterial Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818104.ch11
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Colonization of the urogenital mucosa by . Initial bacterial adherence to the urethral or cervical mucosa is mediated by gonococcal pili. Gonococcal pili are composed of the antigenically variable pilin subunit PilE and several pilin-associated proteins, including the tip-associated adhesin PilC (reviewed in reference ). Adherence to the CD46 receptor via the tip-associated PilC adhesin is depicted, although it has not yet been reported if the PilC adhesin binds to this receptor. Adherence capabilities are also inherent in the PilE subunit ( ). Binding between Opa proteins and members of the CD66 family expressed on epithelial cells can occur w i t h or without uptake, depending on the particular Opa protein and CD66 receptor involved. Opamediated adherence to CD66 receptors on neutrophils can result in nonopsonic uptake. Opa proteins differ in the capacity to bind to various members of the CD66 family, thereby conferring tropism for different cells. Some Opa proteins utilize heparin sulfate molecules to mediate invasion of epithelial cells; entry via Opa protein-heparin sulfate-vitronectin interactions has also been reported (reviewed in reference ). Expression of gonococcal pili, Opa proteins, and LOS undergoes phase and antigenic variation. This characteristic is represented by gonococci having different combinations of these molecules and expressing LOSs of different lengths. Binding of a gonococcal LOS variant expressing a terminal lacto-N-neotetraose molecule to the asialoglycoprotein receptor (ASPG-R) is also shown ( ). Sialylation of the terminal galactose in this tetrasaccharide, an event that is catalyzed by the gonococcal sialyltransferase (STase) ( ), blocks gonococcal epithelial cell invasion by an unknown mechanism ( ). Intracellular replication and survival are enhanced by the cleavage of LAMP1, a late endosomal maturation protein, by IgAl protease ( ). A nonpiliated gonococcus is shown traversing the cell, based on reports that piliation impedes traversal ( ) or is lost ( ) during this process. Passage of the gonococcus to the subepithelium may ultimately provide access to the bloodstream, leading to DGI.

Citation: Jerse A. 2000. : Adaptation and Survival in the Urogenital Tract, p 201-227. In Nataro J, Blaser M, Cunningham-Rundles S (ed), Persistent Bacterial Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818104.ch11
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Cyclical fluctuation of host factors that may challenge the survival of during infection of the female genital tract. Shading is used to illustrate relative differences in mucus viscosity ( ), commensal flora ( ), and local concentrations of reproductive hormones ( ), lactoferrin ( ), and secretory IgA ( ). Light shading is used to represent a pH of < 7 ; moderate shading represents neutral pH. The pH of vaginal mucus is based on a reported pH value of 4.6 (range, 3.3 to 7.4) on days 9 and 10 and 4.4 (range, 3.6 to 6.0) on days 22 to 24 of the cycle. Cervical mucus pH is based on a reported average of 6.8 (range, 5.5 to 8.0) on days 9 and 10 and 6.1 (range, 5.1 to 8.4) on days 22 and 24 ( ). In a study of 50 women with cervical gonorrhea, the cervical mucus pH ranged from 6.8 to 7.6 during the proliferative stage (days 6 to 12), 5.2 to 6.6 during the secretory phase (days 20 to 25), and 4.8 to 7.4 just prior to and during menses (days 26 to 5) ( ).

Citation: Jerse A. 2000. : Adaptation and Survival in the Urogenital Tract, p 201-227. In Nataro J, Blaser M, Cunningham-Rundles S (ed), Persistent Bacterial Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818104.ch11
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Interaction between and polymorphonuclear leukocytes. (A) Phagocytes recruited to the mucosal surface can take up in the absence of opsonins via interactions between Opa proteins and the neutrophil CD66 receptor. An Opa-negative variant that has escaped this interaction is shown; variants expressing some Opa proteins within the Opa repertoire of a strain also do not adhere to neutrophils (reviewed in reference ). LOS sialylation catalyzed by gonococcal sialyltransferase (STase) inhibits Opa-mediated uptake by phagocytes ( ). (B) Stimulation of the phagocyte respiratory burst leads to the production of toxic oxygen radicals. Unlike many other bacteria, does not make superoxide dismutase, which could neutralize the respiratory burst at an early stage in toxic radical production. does produce high levels of catalase, which is capable of cleaving H2O2 to oxygen and water ( ). Increased production of gonococcal catalase occurs in response to sublethal concentrations of H2O2 ( ). (C) The gonococcus may effectively compete with the neutrophil for molecular O2 , which is limited on mucosal surfaces. Lactate produced by neutrophils or by commensal lactobacilli may give the gonococcus a competitive edge in that O2 is rapidly consumed during lactose utilization by ( ; reviewed in reference ). T h e resultant anaerobic environment increases activity and also the expression of LOS species carrying the lactose-N-tetraose molecule to which sialic acid is added, which together may help prevent phagocytosis ( ) (panel A). (D) Oxygen-independent killing mechanisms include the production of catliepsin G, a protease found in neutrophil lysozomes that inhibits gonococcal growth. The targets of catliepsin G are the bacterial transpeptidases used in peptidoglycan synthesis ( ) is resistant to neutrophil defensins ( ). Some gonococcal strains may utilize the lactoferrin released from neutrophil granules as a growth substrate (reviewed in reference ). An additional gonococcal defense that is not shown is the capacity of to directly impair phagocyte functions, including degranulation, actin polymerization, and phagocytosis, through insertion of its major porin, P.I, into the eukaryotic cell membrane ( ). This direct attack on neutrophils may further promote persistence during inflammation.

Citation: Jerse A. 2000. : Adaptation and Survival in the Urogenital Tract, p 201-227. In Nataro J, Blaser M, Cunningham-Rundles S (ed), Persistent Bacterial Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818104.ch11
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