Neisseria gonorrhoeae (Gonococcus)


Neisseria gonorrhoeae is the causative agent of gonorrhea , an infection of the genitourinary tract mucous membranes and of the mucosa of the rectum, oropharynx, and conjunctiva. Gonorrhea transmitted by sexual contact or perinatally is second only to chlamydial infections in the number of cases reported to the U.S. Centers for Disease Control and Prevention (CDC). This high prevalence and the development of antibiotic-resistant strains have led to significant morbidity.

Etiology

Neisseria gonorrhoeae is a nonmotile, aerobic, non–spore-forming, gram-negative diplococcus with flattened adjacent surfaces. Optimal growth occurs at 35-37°C (95-98.6°F) and at pH 7.2-7.6 in an atmosphere of 3–5% carbon dioxide. The specimen should be inoculated immediately onto fresh, moist, modified Thayer-Martin or specialized transport media, because gonococci do not tolerate drying. Thayer-Martin medium contains antimicrobial agents that inhibit hardier normal flora present in clinical specimens from mucosal sites that may otherwise overgrow gonococci. Presumptive identification may be based on colony appearance, Gram stain appearance, and production of cytochrome oxidase. Gonococci are differentiated from other Neisseria spp. by the fermentation of glucose but not maltose, sucrose, or lactose. Gram-negative diplococci are seen in infected material, often within polymorphonuclear leukocytes (PMNs).

As with all gram-negative bacteria, N. gonorrhoeae possesses a cell envelope composed of an inner cytoplasmic membrane, a middle layer of peptidoglycan, and an outer membrane. The outer membrane contains lipooligosaccharide ( LOS ; also called endotoxin ), phospholipid, and a variety of proteins that contribute to cell adherence, tissue invasion, and resistance to host defenses. Systems previously used to characterize gonococcal strains included auxotyping and serotyping. Auxotyping is based on genetically stable requirements of strains for specific nutrients or cofactors as defined by an isolate's ability to grow on chemically defined media. Serotyping systems were based on specific monoclonal antibodies directed against a porin protein called PorB (formerly Protein I or PorI), a trimeric outer membrane protein that makes up a substantial part of the gonococcal envelope structure. Changes in PorB proteins present in a community are believed to result, at least in part, from selective immune pressure. DNA-based typing methods have now supplanted auxo- and serotyping. Older gel-based DNA-based typing methods that included restriction fragment length polymorphism (RFLP) analysis of genomic DNA or rRNA (ribotyping), or typing of genes encoding opacity protein ( opa ) were labor intensive and sometimes lacked the ability to accurately discriminate among strains. Methods currently used include the Neisseria gonorrhoeae multiantigen sequence typing ( NG-MAST ), which examines the sequences of the variable internal fragments of 2 highly polymorphic N. gonorrhoeae genes ( porB encoding PorB and tbpB encoding subunit B of transferrin-binding protein), and multilocus sequence typing ( MLST ), which analyzes the sequences of 7 chromosomal housekeeping genes.

Epidemiology

Since gonorrhea became a nationally notifiable disease in 1944, U.S. rates have ranged between a historic high of 467.7 cases per 100,000 population in 1975 and a historic low of 98.1 per 100,000 in 2009. However, rates have increased almost every year since 2009, with a total of 555,608 cases and a rate of 171.9/100,000 reported in 2017. Rates of reported gonorrhea are also highest in the South (194.0/100,000); among young adults age 20-24 (684.8 cases per 100,000 females age 20-24; 705.2 cases per 100,000 males age 20-24); among males (169.7/100,000 males vs 120.4/100,000 females); and among blacks (548.1/100,000 vs 66.4/100,000 among whites). During 2013–2017, the rate among males increased 86.3% and the rate among females increased 39.4%, suggesting either increased transmission or increased case ascertainment (e.g., through increased extragenital screening) among gay, bisexual, and other men who have sex with men (MSM).

Molecular typing methods (e.g., NG-MAST, MLST) are used to analyze the spread of individual strains of N. gonorrhoeae within a community. Maintenance and subsequent spread of gonococcal infections in a community are sustained through continued transmission by asymptomatically infected people and also by a hyperendemic, high-risk core group such as commercial sex workers, MSM, or adolescents with multiple sexual partners. This latter observation reflects that most persons who have gonorrhea cease sexual activity and seek care, unless economic need or other factors (e.g., drug addiction) drive persistent sexual activity. Thus, many core transmitters belong to a subset of infected persons who lack or ignore symptoms and continue to be sexually active, underscoring the importance of seeking out and treating the sexual contacts of infected persons who present for treatment. Oral sex has a role in sustaining gonorrhea in MSM by providing a pool of untreated asymptomatic pharyngeal infections and may account for as much as one third of symptomatic gonococcal urethritis in MSM.

Gonococcal infection of neonates usually results from peripartum exposure to infected exudate from the cervix of the mother. An acute infection begins 2-5 days after birth. The incidence of neonatal infection depends on the prevalence of gonococcal infection among pregnant women, prenatal screening for gonorrhea, and neonatal ophthalmic prophylaxis.

Pathogenesis and Pathology

N. gonorrhoeae infects primarily columnar epithelium, because stratified squamous epithelium is relatively resistant to invasion. Mucosal invasion by gonococci results in a local inflammatory response that produces a purulent exudate consisting of PMNs, serum, and desquamated epithelium. The gonococcal LOS (endotoxin) exhibits direct cytotoxicity, causing ciliostasis and sloughing of ciliated epithelial cells. Tumor necrosis factor (TNF) and other cytokines are thought to mediate the cytotoxicity of gonococcal infections. LOS activates complement, which also contributes to the acute inflammatory response.

Gonococci may ascend the urogenital tract, causing urethritis or epididymitis in postpubertal males and acute endometritis, salpingitis, and peritonitis (collectively termed acute pelvic inflammatory disease or PID) in postpubertal females. Dissemination from the fallopian tubes through the peritoneum to the liver capsule results in perihepatitis (Fitz-Hugh–Curtis syndrome). Gonococci that invade the lymphatics and blood vessels may cause inguinal lymphadenopathy; perineal, perianal, ischiorectal, and periprostatic abscesses; and disseminated gonococcal infection (DGI).

A number of gonococcal virulence and host immune factors are involved in the penetration of the mucosal barrier and subsequent manifestations of local and systemic infection. Selective pressure from different mucosal environments probably leads to changes in the outer membrane of the organism, including expression of variants of pili, opacity or Opa proteins (formerly protein II), and LOS. These changes may enhance gonococcal attachment, invasion, replication, and evasion of the host's immune response.

For infection to occur, the gonococcus must first attach to host cells. Gonococci adhere to the microvilli of nonciliated epithelial cells by hairlike protein structures (pili) that extend from the cell wall. Pili undergo high-frequency antigenic variation that may aid in the organism's escape from the host immune response and may provide specific ligands for different cell receptors. Opacity proteins, most of which confer an opaque appearance to colonies, function as ligands for members of the carcinoembryonic antigen–related cell adhesion molecule ( CEACAM ) family of proteins or heparin sulfate proteoglycans (HSPGs) to facilitate binding to human cells. Interactions between complement receptor 3 (CR3) on cervical epithelial cells and iC3b, pili, and PorB on the gonococcal surface facilitates cellular entry of gonococci in women. In contrast, the interaction between LOS and asialoglycoprotein receptor (ASGP-R) permits gonococcal entry into male urethral epithelial cells. Gonococci that express certain Opa proteins adhere to CEACAM3 and are phagocytosed by human neutrophils in the absence of serum. The interaction of Opa with CEACAM1 on CD4 + T lymphocytes may suppress their activation and proliferation and contribute to the immunosuppression associated with gonorrhea. A gonococcal IgA protease inactivates IgA 1 by cleaving the molecule in the hinge region and could contribute to colonization or invasion of host mucosal surfaces.

Other phenotypic changes that occur in response to environmental stresses allow gonococci to establish infection. Examples include iron-repressible proteins for binding transferrin or lactoferrin, anaerobically expressed proteins, and proteins that are synthesized in response to contact with epithelial cells. Gonococci may grow in vivo under anaerobic conditions or in an environment with a relative lack of iron.

Approximately 24 hr after attachment, the epithelial cell surface invaginates and surrounds the gonococcus in a phagocytic vacuole. This phenomenon is thought to be mediated by the insertion of the gonococcal outer membrane PorB into the host cell, causing alterations in membrane permeability. Subsequently, phagocytic vacuoles begin releasing gonococci into the subepithelial space by means of exocytosis. Viable organisms may then cause local disease (i.e., salpingitis) or disseminate through the bloodstream or lymphatics.

Serum IgG and IgM directed against gonococcal proteins and LOS activate complement on gonococci. Gonococci have evolved several mechanisms to dampen complement activation. Scavenging cytidine monophospho- N -acetyl neuraminic acid (CMP-Neu5Ac, the donor molecule for sialic acid) to sialylate its LOS is one such example, which reduces binding of bactericidal antibodies and simultaneously enhances binding of a complement inhibitor called factor H (FH). This property is often lost on subculturing gonococci on media that lacks CMP-Neu5Ac and is thus termed “unstable serum resistance.” In contrast, “stable serum resistance”(complement resistance independent of LOS sialylation) is often seen in gonococci that express particular porin proteins (most PorB.1As and select PorB.1Bs),which enables them to bind to complement inhibitors such as FH and C4b-binding protein (C4BP). Such strains are often associated with disseminated disease. N. gonorrhoeae differentially subverts the effectiveness of complement and alters the inflammatory responses elicited in human infection. Isolates from cases of DGI typically are “stably” serum resistant, show less C3b deposition on their surface, inactivate C3b more rapidly, generate less C5a, and result in less inflammation at local sites. PID isolates are serum sensitive, deposit more C3b on their surface, inactivate C3b relatively slowly, generate more C5a, and result in more inflammation at local sites. IgG antibody directed against gonococcal reduction-modifiable protein ( Rmp ) blocks complement-mediated killing of N. gonorrhoeae. Anti-Rmp blocking antibodies may harbor specificity for outer membrane protein (e.g., OmpA) sequences shared with other Neisseria spp. or Enterobacteriaceae, may be directed against a unique Rmp sequence upstream of the OmpA-shared region that includes a cysteine loop, or both. Preexisting antibodies directed against Rmp facilitate transmission of gonococcal infection to exposed women; Rmp is highly conserved in N. gonorrhoeae, and the blocking of mucosal defenses may be one of its functions. Gonococcal adaptation also appears to be important in the evasion of killing by neutrophils. Examples include sialylation of LOS, increases in catalase production, and changes in the expression of surface proteins.

Host factors may influence the incidence and manifestations of gonococcal infection. Prepubertal girls are susceptible to vulvovaginitis and rarely experience salpingitis. N. gonorrhoeae infects noncornified epithelium, and the thin noncornified vaginal epithelium and alkaline pH of the vaginal mucin predispose this age group to infection of the lower genital tract. Estrogen-induced cornification of the vaginal epithelium in neonates and mature females resists infection. Postpubertal females are more susceptible to salpingitis, especially during menses, when diminished bactericidal activity of the cervical mucus and reflux of blood from the uterine cavity into the fallopian tubes facilitate passage of gonococci into the upper reproductive tract.

Populations at risk for DGI include asymptomatic carriers; neonates; menstruating, pregnant, and postpartum women; MSM; and individuals with defects in complement. The asymptomatic carrier state implies failure of the host immune system to recognize the gonococcus as a pathogen, the capacity of the gonococcus to avoid being killed, or both. Pharyngeal colonization has been proposed as a risk factor for DGI. The high rate of asymptomatic infection in pharyngeal gonorrhea may account for this phenomenon. Women are at greater risk for development of DGI during menstruation, pregnancy, and the postpartum period, presumably because of the maximal endocervical shedding and decreased peroxidase bactericidal activity of the cervical mucus during these periods. A lack of neonatal bactericidal IgM antibody is thought to account for the increased susceptibility of neonates to DGI. Persons with terminal complement component deficiencies (C5-C9) are at considerable risk for development of recurrent episodes of DGI.

Clinical Manifestations

Gonorrhea is manifested by a spectrum of clinical presentations from asymptomatic carriage, to the characteristic localized mucosal infections, to disseminated systemic infection (see Chapter 146 ).

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