Chlamydia trachomatis

Chlamydia cases in Wisconsin 1965-1991 (cases per 100,000 people, by year, according to sex and age)

History and Biological Background

Chlamydia is caused by the bacterium Chlamydia trachomatis. The word chlamys is Greek for "cloak draped around the shoulder." This describes how the intracytoplasmic inclusions caused by the bacterium are "draped" around the infected cell's nucleus. Because the symptoms of the disease resemble other pathologies, chlamydia was not recognized as a sexually transmitted disease until recently. Isolation from embryonated eggs in 1957 and from cell culture in 1963 confirmed its existence as a bacterium. However, since the organism is an obligate intracellular parasite that exclusively infects humans (it cannot synthesize its own ATP or grow on artificial medium), it was once thought to be a virus. Because of Chlamydia's unique developmental cycle, it was taxonomically classified in a separate order. It can thus be found with the other well-known intracellular parasites, rickettsiae, in diagnostic manuals. Chlamydia has a genome size of approximately 500-1000 kilobases and contains both RNA and DNA. The organism is also extremely temperature sensitive and must be refrigerated at 4 C as soon as a sample is obtained.

Virulence Factors

There are numerous factors that contribute to the pathogenicity of Chlamydia trachomatis. Colonization of Chlamydia begins with attachment to sialic acid receptors on the eye, throat, or genitalia. It persists at body sites that are inaccessible to phagocytes, T-cells, and B-cells. It also exists as 15 different serotypes. These serotypes cause four major diseases in humans: endemic trachoma (caused by serotypes A and C), sexually transmitted disease and inclusion conjunctivitis (caused by serotypes D and K), and lymphogranuloma venereum (caused by serotypes L1, L2, and L3). Endemic trachoma leads to blindness, whereas inclusion conjunctivitis is associated with the sexually transmitted form and does not lead to blindness. Its unique cell wall structure is another virulence factor. Studies reveal that Chlamydia, because of its cell wall, is able to inhibit phagolysosome fusion in phagocytes. The cell wall is proposed to be gram-negative in that it contains an outer lipopolysaccharide membrane, but it lacks peptidoglycan in its cell wall. This lack of peptidoglycan is shown by the inability to detect muramic acid and antibodies directed against it. It may, however, contain a carboxylated sugar other than muramic acid. The proposed structure consists of a major outer membrane protein cross-linked with disulfide bonds. It also contain cysteine-rich proteins (CRP) that may be the functional equivalent to peptidoglycan. This unique structure allows for intracellular division and extracellular survival (Hatch 1996).

Model of chlamydial cell wall or envelope

Vaccines

The surface of chlamydia does not contain proteins that are distinctive enough to induce a full immune response. The cell wall does contain an exoglycolipid antigen that induces a weak immune response (for reasons unknown, the immune response is weaker to carbohydrate antigens). This is the basis for a recent vaccine developed by researchers at Johns Hopkins University. The researchers are developing a protein version of the antigen by injecting C. trachomatis into mice, isolating and amplifying the antibodies produced, and then using these antibodies to "mold" a protein resembling the exoglycolipid antigen (Coghian 1996). The next step is to adapt the procedure to humans.

Life Cycle

The life cycle of C. trachomatis consists of two stages: elementary body and reticulate body. The elementary body is the dispersal form and is analogous to a spore. It is approximately 0.3 um in diameter and induces its own endocytosis upon exposure to target cells. It is this form that prevents phagolysosomal fusion and hence allows for intracellular survival. Once inside the endosome, the glycogen produced causes the elementary body to "germinate" into the vegetative form, the reticulate body. This form divides by binary fission at approximately 2-3 hours per generation. It has an incubation period of 7-21 days in the host. It contains no cell wall and (when stained with iodine) is detected as an inclusion in the cell. After division, the reticulate body transforms back to the elementary form and is released by the cell by exocytosis. One phagolysosome usually produces 100-1000 elementary bodies.

The infectious life cycle of Chlamydia (after R.C. Barnes)

Transmission and Symptoms

Chlamydia is transmitted through infected secretions only. It infects mainly mucosal membranes, such as the cervix, rectum, urethra, throat, and conjunctiva. It is primarily spread via sexual contact and manifests as the sexually transmitted disease. The bacterium is not easily spread among women, so the STD is mainly transmitted by heterosexual or male homosexual contact. However, infected secretions from the genitals to the hands and eventually to the eyes can cause trachoma.

Symptoms due to this contact are quite variable. In fact, 75% of women and 25% of men with Chlamydia show no symptoms at all. In women, symptoms include increased vaginal discharge, burning during urination, irritation of the area around the vagina, bleeding after sexual intercourse, lower abdominal pain, and abnormal vaginal bleeding. Infection in women usually begins at the cervix. In men, non-gonococcal urethritis is the main symptom. This includes clear, white, or yellow discharge from the urethra, burning and pain during urination, and tingling or itching sensations. Another infection caused by C. trachomatis, lymphogranuloma venereum, is characterized by a swelling of the lymph nodes in the groin area. In men, this can lead to proctitis and in women, it can lead to rectal narrowing. The primary stage is detected as small ulcers or vesicles which usually heal without scarring. The secondary stage, called "supperative lymphadenopathy", is characterized by chills, fever, and arthralgais. The large area of swelling in the groin is called a bubo. Finally, the tertiary stage is when rectal narrowing or draining of the sinuses occurs.

Diagnostic Tests

Detection of the bacterium can be accomplished using both non-culture and culture tests. Non-culture tests include the following:

• Fluorescent Monoclonal Antibody Test: detects either the major outer membrane protein or the LPS
• Enzyme immunoassay: detects a colored product converted by an enzyme linked to an antibody
• DNA probes: uses DNA complementary to specific ribosomal RNA sequences
• Rapid Chlamydia tests: uses antibodies against the LPS
• Leukocyte esterase tests: detects enzymes produced by leukocytes containing the bacteria in urine

Nucleic acid amplification using polymerase chain reaction and ligase chain reaction are also under experimentation. Unfortunately, certain non-culture tests are not specific and hence cause false positive readings to occur. Similarly, antibodies can cross-react with non-chlamydial species.

Culture tests identify intracytoplasmic inclusions in cells stained with monoclonal fluorescent antibodies. The cells are subsequently amplified on cyclohexamide-treated McCoy cells (a mouse cell line easily infected with the bacterium). Unlike non-culture tests, culture tests are 100% specific. Disadvantages are that it requires 3-7 days to obtain results, is technically difficult, requires special transport media, and is subject to contamination. Similarly, sample collection, if delayed more than 48 hours, requires storage at -70 C. Because Chlamydia is normally found in association with the normal flora, samples must be treated with gentamycin to kill other microorganisms. Dead microorganisms or effect of the gentamycin on chlamydia may bias results.

Intracellular Inclusions of C. trachomatis (after R.C. Barnes)

Treatment

Treatment of chlamydia is accomplished with various antibiotics. Doxycycline is the antibiotic of choice because it is used for extended treatment, can be taken with food, and is inexpensive. However, tetracycline, chloramphenicol, rifampicin, and fluroquinones can also be used. Pregnant women are advised to take erythromycin for the infection. Recently, azithromycin has been proven as an effective single-dose therapy. Hence, this improves patient compliance, but is more expensive than the other antibiotics. It is essential to note that sex partners should be involved in a treatment regime as well.

Prevention

Unfortunately, literature on Chlamydia stresses treatment instead of prevention. Because Chlamydia is a completely preventable disease, this should be the focus of health care and research facilities. Prevention strategies include personal strategies, community-based strategies, and health-care provider strategies (CDC 1993).

1. Personal Strategies

   Personally, it is important to see a health care provider regularly. Because chlamydia is markedly asymptomatic, routine visits to a health care facility may be the only way for detection. It is also essential to refer sexual partners for testing and treatment if one has been diagnosed with chlamydia. Other behavioral changes include using condoms during sex, delaying the age of first intercourse, monogamy, discussing sexual history with partners, and educating yourself about sexually transmitted diseases and sharing this information with friends.

2. Community-Based Strategies

   Community-based strategies include public awareness, HIV and STD risk reduction programs, school involvement, and targeting out-of-school adolescents through vocational training centers, detention centers, and recreation programs. Schools can provide rates of the disease, its adverse symptoms and consequences, information on treatment for sex partners, and where and how to obtain care. Role playing in health classes can also be used to stress how to tell a partner of infection and how to find care for the infection.

3. Role of Health Care Providers

   Health care providers need to be more aware and recognize symptoms of Chlamydia. Because most chlamydia infections look like a bladder infection, this is difficult. Similarly, providers should arrange for treatment of sex partners, counsel patients on the risk of STDs, and screen at-risk patients.

4. Wisconsin's Control Program

   Wisconsin currently has a control program organized by Madison's Laboratory of Hygiene, Milwaukee's Bureau of Laboratories, and Planned Parenthood Inc. This program features selective screening, low-cost and high-volume testing, notification and treatment of infected partners, education of health care providers, and epidemiological methods to identify at-risk groups. It emphasizes coordinating private facilities and public programs to control the disease. This includes case reporting and notification of infected partners by private facilities to the public sector. The program is also working to identify the most effective methods of sampling and detecting chlamydial infection (Hillis et al.)

Social Issues of Chlamydia

Chlamydia is a socially transmitted disease. Thus, medical intervention cannot be the only solution to control infection rates. Social factors, including behavioral changes and consistent access to quality health care, need to be included to eradicate this preventable disease. Because Chlamydia often shows no symptoms, it is likely to be left untreated. Complications in men can lead to fever, testicular pain and swelling, and inflammation of the epididymis. Subsequent scarring of the epididymis can lead to infertility. In women, complication include post-partum fever, ectopic pregnancy (pregnancy outside of the uterus), and pelvic inflammatory disease (PID). PID is an infection of the fallopian tubes, ovaries, and/or uterus that is characterized by lower abdominal pain, painful sex, increased pain during menstruation, irregular menstruation, fever, and chills. Scarring from PID may cause infertility. Statistics show that one chlamydial infection can lead to a 12% chance of infertility, two Chlamydia infections can lead to a 40% chance of infertility, and three Chlamydial infections can lead to an 80% chance of infertility. In addition, transmission from mother to infant during labor can cause trachoma for the infant. Scarring from this disease can ultimately lead to blindness.

Numerous risk groups and behaviors have been associated with Chlamydia. Risk factors include age (40% of adolescent women are currently infected), inner city living, low socioeconomic status, African-American descent, and co-infection with either N. gonorrhoeae or Trichomonas. Behavioral risks include unprotected sex with an infected partner and multiple partners.

Finally, decreased access to quality, consistent care can be a factor in preventing and treating Chlamydia. Often, cost can be a problem. However, most places are free or offer low-cost services to diagnose and treat the disease (the Blue Bus STD clinic at UW-Madison offers free, anonymous testing). Statistics show that women not tested for Chlamydia are twice as likely to develop PID. Information on STDs can be obtained from hotlines, Planned Parenthood Inc., community health agencies, or a counselor or family physician. Issues of confidentiality and respectful care also need to be addressed. Many health care facilities may be legally bound to report untreated cases or notify partners. However, it is essential that individuals take this responsibility since most facilities do not follow through with case reporting. Many doctors may see Chlamydia as the right punishment for casual/immoral sex. This is an issue especially for lower classes, minorities, and homosexuals. In addition, women may be labeled "promiscuous." Women internalize these feelings of guilt and thus do not seek further treatment or notify partners. Because of current views of women by the health care system, symptoms of Chlamydia are often misdiagnosed or overlooked. One woman experienced abdominal pain for nine months. It was not until her husband was diagnosed with chlamydia did she receive proper treatment (The Boston Women's Health Collective 1992). Issues of sexism, racism, and classism need to be eradicated to ensure quality, unbiased medical care.

The STD hotline is: 1-800-227-8922

Chlamydia can be eradicated if behavioral modifications are implemented. By adopting strategies outlined above, not only will chlamydia rates begin to fall, but also rates of other sexually transmitted diseases. These modifications are essential in the current epidemic of the most severe sexually transmitted disease, AIDS. Unnecessary costs for sexually transmitted diseases can be eliminated if people begin taking responsibility for their actions. Thus, time and money being spent on completely preventable diseases, such as chlamydia, can be more efficiently allocated for infallible diseases and social problems.

References

1. Barnes, R.C. (1990). Infections Caused by Chlamydia trachomatis Chapter 6 in Morse, et al, Sexually Transmitted Diseases. J.B. Lippincott. Philadelphia

2. The Boston Women's Health Collective (1992). The New Our Bodies Ourselves. New York: Simon and Schuster.

3. CDC. Recommendations for the Prevention and Management of Chlamydia trachomatis Infections. MMWR 1993; 42 (RR-12).

4. Coghlan, Andy (1996). Shapely Vaccine Targets Chlamydia. New Scientist. 152: 18.

5. Hatch, Thomas P. (1996). Disulfide Cross-Linked Envelope Proteins: the Functional Equivalent of Peptidoglycan in Chlamydia? Journal of Bacteriology. 178: 1-5.

6. Hillis, Susan et al. (1995). Impact of a Comprehensive Chlamydia Prevention Program in Wisconsin. Family Planning Perspectives. 27: 108-111.

7. Madigan, Michael, Martinko, John, and Jack Parker (1997). Brock's Biology of Microorganisms. eighth edition. New Jersey: Prentice Hall.