by Yen Lemire
Neisseria gonorrhoeae is the obligate human pathogen that causes the sexually transmitted disease (STD) gonorrhea. This Gram-negative diplococci/gonococci does not infect other animals or experimental animals and does not survive freely in the environment. The gonococcal infection occurs in the upper or lower tract, pharynx, ophthalmic area, rectum, and bloodstream. During the 1980’s gonorrhea was also referred to as “the clap” when public awareness was quite minimal. This was one of the venereal diseases prostitutes hoped to contract since it resulted in infertility by pelvic inflammatory disease (PID). As documentation, diagnostic testing, and public awareness improved, there has been a decline in incidence reports, however, it is still considered a very common infectious disease.
Sexually active men and women of all races, ages, and socioeconomic backgrounds are susceptible to the gonococcal infection. However, out of the infected population, the CDC states 80% of the females and 10% of the males are asymptomatic. After incubation of five to seven days, males tend to display symptoms of swelling in the urethra, painful and more frequent urination, and abnormal penal discharge of a thick yellow exudate (pus). Similarly, females experience chronic abdominal pain, inflammation of the cervix, painful urination, bleeding or irregular menstrual cycles, fever and increased vaginal yellow discharge. Females have a higher risk factor of 60-90% of being infected after a single sexual encounter. Both sexes experience sore throat in oral infections if they are not asymptomatic. However, this response is most commonly mistaken as a viral sore throat.
Neisseria gonorrhoeae does not thrive in the environment and grows in a CO2 environment, therefore, the urethra, cervix, rectum, and throat are the main sites of infection. Once the gonococci gain entrance into the mucous membranes of these areas, they target columnar non-ciliated epithelial cells. Neisseria gonorrhoeae uses a type IV pilus (twitches, forms bundles and able to take up DNA) to anchor itself at the infection site. The pilE gene has been found to be the main factor for adherence to epithelial cells. In a study, missense mutations of the pilE gene revealed altered fiber morphology. PilE mutants had a defect in filament assembly, hence, less adherence to human epithelial cells. In a wild type sample there are significant interconnections of cells, then compared to a sample with a missense PilE polypeptide, we can see reduced interconnections of the cells and filamentous structure. These defects only are expressed when the pilT gene is activated.
Spread occurs via oral, vaginal, and anal sexual contact through the routes of penis-vagina, penis-mouth, penis-anus, mouth-vagina, and mouth-anus. During childbirth, infants contract the infection in the birth canal resulting in bilateral conjunctivitis. Intimate contact is required to infect another person, therefore, the myth of contracting the disease by toilet seats is a myth.
Replication of gonococci begin with the adherence to non-ciliated cells resulting in death triggered by the lipopolysaccharide (LPS). Once the ciliary beat is impaired, the bacteria cannot be cleared from the mucosal membrane. The gonococci undergo parasite-directed endocytosis where they are taken up by the microvilli of the non-ciliated cells acting like phagocytes. Inside the cell, the gonococci replicate within vacuoles that combine into larger vacuoles. Here they can avoid phagocytosis, antibodies, and ant microbial agents. These larger vacuoles transport the gonococci to the base of the non-ciliated cells where they will be exocytosed into subepithelial tissue creating inflammation or disseminating into the bloodstream.
Response to host defense
Once a host is infected with Neisseria gonorrhoeae, they do not build up an immune to reinfection. Neisseria gonorrhoeae has the capability of antigenic variation where it can rearrange proteins on its surface. Pilin genes like pilE, pilT, and pilS expressed at one point can be altered due to the high rate of genetic rearrangement producing new variants. Expression of a new serotypes of the altered bacterial gene makes it possible to evade the host immune response. Opa proteins are surface proteins that have a critical role in the adhesion to epithelial, endothelial cells and polymorphonuclear neutrophils. It has been found that Opa proteins bind to the carcinoembryonic antigen-related cellular adhesion molecule 1 (CEACAM1) which is a receptor on the CD4+ lymphocyte. This in turn inactivates the lymphocyte and proliferation is switched off, therefore, hinders the memory of the immune system as well as increased susceptibility to opportunistic pathogens. There is also an IgA1 protease secreted from Neisseria gonorrhoeae that cleaves the IgA1subunit of the IgA immunoglobin that protects the host's mucous membranes. The IgA1 protease has multiple types that cleave IgA1 in the hinge region separating the Fab and Fc regions, therefore, dismantling the host defense mechanism. This protease may also cleave other compounds with similar structure to the hinge area of IgA1.
Transmission is common through anal, vaginal, and oral sex. Core group members that have multiple sex partners are at high risk for acquiring and transmitting gonorrhea. Vertical transmission occurs from mother to child during pregnancy or birth. Consequently, the child contracts gonorrhea in the eyes which can lead to blindness.
A few diagnostic tests can be performed to detect Neisseria gonorrhea. A Gram stain of the discharge can confirm a Gram-negative diplococci. Enzyme-linked immunosorbent assay (ELISA) is also used as a rapid test and is sensitive to gonorrhea. Uconn’s Women’s Clinic uses the PCR method to detect Neisseria gonorrhea. A urine sample from males and a vaginal swab from females are obtained to perform the diagnostic test. A vaginal sample provides better detection than a urine sample in women.
Piliated gonococci trigger a production and release of cytokines; this release causes a heavy inflammation reaction. LPS and peptidoglycan are most likely the factors for the host immune response. The non-ciliated epithelial cells are destroyed and sloughed off. Disseminated gonococcal infection (DGI) is rare but can cause septic arthritis and tenosynovitis (inflammation of a tendon sheath). Dissemination into the blood stream occurs from infections of the genitalia, pharynx, or rectum where the gonococci target the joints, synovial fluid, and skin. DGI seems to affect pregnant women more than non-pregnant. This is due to the hormone human Chorionic Gonadotropin (hCG) that is stimulated by progesterone during pregnancy. hCG serves to maintain the fetus and can prevent evasion from host defenses. The IgA1 protease can cleave hCG because it has a similar structure to the hinge area of IgA1 immunoglobin, therefore pregnant women have a weakened defense system.
Women tend to be more asymptomatic based on a complement receptor 3 (CR3). This receptor has been localized in cervical epithelial cells, which does not activate an inflammatory response. An alternate effect is a ruffling of cell membranes when Neisseria gonorrhoeae infects the cervical epithelium. This adverse effect suppresses the inflammation response and seems to be the cause why women with gonorrhea asymptomatic. The CR3 is absent in the male urogenital tract and when infected with Neisseria gonorrhoeae, there is no membrane ruffling. In contrast, infected males have an inflammatory response in the urethra. This CR3 could be the main contribution to women developing PID, ectopic pregnancy, scarring, and infertility.
Untreated gonococcal infections in males may lead to complications of the testicles and prostate followed by scarring of the tissue resulting in sterility. Untreated gonorrhea in women can result in pelvic inflammatory disease and subsequent infertility, ectopic pregnancy, and chronic pelvic pain. In addition, substantial evidence suggests that gonorrhea facilitates the transmission of HIV infection in both men and women. Those infected by Neisseria gonorrhoeae are usually also treated for Chlamydia trachomatis are prescribed Ceftriaxone and doxycycline or azithromycin. Antibiotics that affect cell wall and DNA synthesis have been ineffective due to resistant strains on the rise. However, pregnant women diagnosed with gonorrhea are given ceftriaxone or cefixime. Vaccines are unsuccessful in preventing the infection of gonorrhea due to various surface antigens that prevent the development of an effective vaccine. However, Opa proteins have been considered as a target for a vaccine.
Neisseria gonorrhoeae has existed for a long time and does not discriminate between the sexes, age groups or economical status causing a worldwide problem. Public awareness has introduced many programs attempting to prevent an increased incident rate. All sexually active individuals should be tested on an annual basis as well as take many preventative measures such as condom use and modify sexual behavioral habits.
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© 2010, J.Graf. Site made by Yen Lemire, for comments please contact Joerg.Graf@uconn.edu