• Chlamydia;
  • female reproduction;
  • pathogenesis;
  • vaccine


  1. Top of page
  2. Abstract
  3. Introduction
  4. Chlamydia infection and immunity
  5. Treatment or Prevention?
  6. Problems with Vaccine Development
  7. Conclusions
  8. Acknowledgments
  9. References

Citation Carey AJ, Beagley KW. Chlamydia trachomatis, a hidden epidemic: effects on the female reproduction and options for treatment. Am J Reprod Immunol 2010

The number of genital tract Chlamydia trachomatis infections is steadily increasing worldwide, with approximately 50–70% of infections asymptomatic. There is currently no uniform screening practice, current antibiotic treatment has failed to prevent the increased incidence, and there is no vaccine available. We examined studies on the epidemiology of C. trachomatis infections, the effects infections have on the female reproductive tract and subsequent reproductive health and what measures are being taken to reduce these problems. Undetected or multiple infections in women can lead to the development of severe reproductive sequelae, including pelvic inflammatory disease and tubal infertility. There are two possible paradigms of chlamydial pathogenesis, the cellular and immunological paradigms. While many vaccine candidates are being extensively tested in animal models, they are still years from clinical trials. With no vaccine available and antibiotic treatment unable to halt the increased incidence, infection rates will continue to increase and cause a significant burden on health care systems.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Chlamydia infection and immunity
  5. Treatment or Prevention?
  6. Problems with Vaccine Development
  7. Conclusions
  8. Acknowledgments
  9. References

Chlamydia trachomatis is a Gram-negative bacterium, which has a unique biphasic developmental cycle. Genital tract C. trachomatis infections, caused by serovars D-K, are the most common bacterial, sexually transmitted infection, costing health care systems billions of dollars to treat not only the acute infections, but also the complications they cause.1 A major concern with Chlamydia infections is that 70% of infected women and 50% of infected men are asymptomatic. In women, this can lead to severe sequelae such as pelvic inflammatory disease (PID), which can then cause ectopic pregnancies and tubal infertility,2,3 and men can suffer from prostatitis and epididymitis.4 Repeat or multiple infections with C. trachomatis increase the likelihood of these same sequelae, with a 2–4.5-fold increase in the risk of ectopic pregnancy, and a 4.5–6.4-fold increase in the chance of PID development.5 Risk factors for contracting infection include age, with those aged 15–24 most affected, gender, with women at more risk than men, and race.6

Recent reports from the Centers for Disease Control and Prevention (CDC) state that, in the United States, there has been an increase in infections of 7.5% from 2006 to 2007.7 It is possible that these increases are attributed to the development of more specific testing procedures;8 however, a study controlling for the effects of new testing methods and demographic and sexual risk behaviors showed an independent 5% per year increase in C. trachomatis positivity between 1997 and 2004.9 Even though the rates of genital tract infections continue to rise, there are no uniformly accepted screening practices, with the majority being opportunistic. Systematic reviews of the cost effectiveness of screening young asymptomatic women suggested screening is cost effective, because of the reduction in long-term health costs.10,11

This highlights that while infection rates continue to increase and cost health care systems billions of dollars annually, there are currently few options available to prevent the increasing incidence of infections. This emphasizes the urgent need for the development of an efficacious vaccine.

Chlamydia infection and immunity

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chlamydia infection and immunity
  5. Treatment or Prevention?
  6. Problems with Vaccine Development
  7. Conclusions
  8. Acknowledgments
  9. References


The primary site of chlamydial infections of the genital tract is the columnar epithelial cells of the endocervix of women and the urogenital epithelia of men.12 In men, ascending infection can cause prostatitis and epididymitis,13 this has been extensively reviewed by Cunningham and Beagley13 and will not be addressed in this review. In women, the infection can ascend the reproductive tract and cause PID and ectopic pregnancies.11 The development of disease sequelae in women following chlamydial infection is associated with ascension of Chlamydia from the lower reproductive tract into the upper reproductive tract. The mechanisms that lead to this ascension are not fully understood, neither is the rate at which this happens. It is thought that Chlamydia can gain access to the URT of women by attachment to sperm.14,15 It is also possible that movement along the reproductive tract is from general flow of fluids (Fig. 1), with studies demonstrating that particles approximately the same size of sperm,16 or radio-labeled sperm,17 deposited into the vagina of women, could be found in the uterus within 2 min, demonstrating that rapid ascension of bacteria could occur.


Figure 1.  The paradigms of chlamydial pathogenesis in the female reproductive tract. Chlamydia ascends the reproductive tract either by attachment to sperm or from the general flow of fluids, infecting the upper female reproductive tract, leading to the development of pathology. Pathogenesis is thought to occur through either an innate, non-immune cellular response (Cellular paradigm), or an antigen-specific adaptive cellular response (Immunological paradigm). Green circles: Chlamydia particles; DTH: Delayed-type hypersensitivity; cHSP-60: chlamydial heat-shock protein-60; PID: Pelvic inflammatory disease; TFI: Tubal factor infertility; TLR: Toll-like receptor; IL: Interleukin; GM-CSF: Granulocyte–macrophage colony-stimulating factor.

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Murine studies using Chlamydia muridarum have greatly expanded the knowledge of infection kinetics, including the differential cell infiltration between the lower and upper genital tract, the rate at which this occurs,18–24 and also the rate of infection ascension.24–26 The infectious dose of Chlamydia is known to modulate the innate immune response, with greater inoculating doses causing a greater innate immune response.26 It has been suggested that because of the greater immune responses elicited by high infectious challenge doses, the infection does not cause as great a degree of hydrosalpinx.26 However, it has also been shown that while the infectious dose affects the degree of ascension of infection along the female reproductive tract of mice, it does not affect the pathological outcomes, such as hydrosalpinx development and cellular infiltrate.24 This suggests that, if a similar situation occurs in humans, the development of pathological sequelae may not be affected by the sexual transmission dose. Although the number of Chlamydia required to establish an infection in different strains of mice27 and the number of Chlamydia caviae transmitted by an infected male guinea pig during mating is known,28 there are no data on these parameters in human infections.


The regulation of immune responses against genital tract Chlamydia trachomatis infections in humans is largely unknown, because of the difficulty in obtaining samples and monitoring patients long term. Natural immunity to a single infection is known to be short lived and serovar specific;29 however, multiple infections with different serovars induces longer term, cross-serovar immunity.30 Immune responses to infections are linked to genetic variations, with specific polymorphisms in immune response genes influencing the magnitude of immune responses to microorganisms.31

There have been reports indicating that women have spontaneously cleared a genital infection without medical intervention; however, the exact duration of an infection cannot be determined.32 It is also believed that antibiotic intervention increases the longer term rates of re-infection because of the inability of the person to develop protective immunity against Chlamydia.33 It is widely accepted, based on animal studies, that to resolve a chlamydial genital tract infection in women, both a Th1 and Th2 response needs to be mounted. The infiltration and activation of CD4+ Th1 cells is required for the development of protective immunity and clearance of a primary infection.34 While clearance of a primary infection is dependent on the development of cell-mediated immunity, clearance of a secondary infection requires the presence and production of antibodies.12,35 Also an increase in infiltration of CD8+ T cells,36 B cells,37 neutrophils38, and dendritic cells39 (DCs) is required. This ensures effective clearance of both the intracellular reticulate bodies and extracellular elementary bodies in the genital tracts of infected individuals. Recent studies examining cytobrush samples from the endocervix demonstrated that women infected with C. trachomatis had an increase in CD3+, CD4+ and CD8+ cells, and neutrophils,40,41 and an increase in recruitment of myeloid and plasmacytoid DCs.41

The first line of defense against a Chlamydia infection within the female reproductive tract is the mucosal barrier. Initial infection of epithelial cells causes a cascade of events leading to the increased production of pro-inflammatory cytokines and chemokines including IL-1, IL-842, IL-1219, IL-6, and GM-CSF,43 which then induces an influx of innate immune cells (Fig. 1) such as natural killer (NK) cells,44 DCs,39 and neutrophils.38 These cells then produce more cytokines such as IFN-γ and TNF-α, which impede further chlamydial growth. Production of various cytokines has, however, proven to be detrimental to the mucosal barrier, with their presence linked to various tissue pathologies,12 and this has been termed the cellular paradigm45 (Fig. 1).

Tissue destruction leading to the development of tubal infertility and ectopic pregnancy is caused by the production of cytokines (Fig. 1), including IL-1 and IL-8, in response to infection.42 Fallopian tube biopsy samples infected with C. trachomatis, with or without IL-1 receptor antagonist present, revealed that the production of IL-1 leads to destruction of the ciliated epithelium.42 Toll-like receptor 2 (TLR-2) has also been implicated in the development of chronic pathology in the mouse model of genital infection,46 with TLR-2 KO mice producing lower levels of TNF-α and MIP-2, and developing significantly less oviduct pathology.46 This supports the idea that it is the host’s immune response to infection that is responsible for the damage rather than the infection itself.

It has also been suggested that the pathologies seen after an infection are linked to antigen-specific adaptive cellular responses, this is termed the immunological paradigm47 (Fig. 1). The exact mechanism or antigen behind the immunological paradigm has yet to be determined. There are conflicting reports that pathogenesis may be linked to chlamydial heat-shock protein-60 (cHSP-60) through delayed-type hypersensitivity (DTH) or molecular mimicry causing autoimmunity. Chlamydia can enter a dormant, persistent state, where, in the absence of a productive infection, there is still a low level of immune stimulation from antigen recognition. This low level stimulation is believed to cause chronic inflammatory cell infiltration.48,49 Originally, guinea pigs sensitized with Triton-X-100 soluble chlamydial elementary bodies (EBs) had greater ocular delayed hypersensitivity when re-exposed to infection at other sites, including vaginal and intestinal infections.50 Similarly, monkeys immunized against C. trachomatis developed a greater follicular response in the eye upon re-exposure than non-immune controls,51 highlighting the significance of repeated infections in terms of a delayed hypersensitivity response. T cells isolated from endometrial and salpingeal tissues, removed from patients with PID and tubal factor infertility (TFI), responded to stimulation with cHSP-60 to a greater degree than with chlamydial EBs, further supporting cHSP-60’s role in DTH52,53 (Fig. 1). The presence of cHSP-60 antibodies has also been correlated with PID severity,54–56 TFI57, and more severe salpingeal pathology.58

It has also been debated as to whether or not autoimmunity plays a role in the pathogenesis of chlamydial infections (Fig. 1), because of the high sequence homology between self and chlamydial HSP-60.48 A study where mice were immunized with either cHSP-60, mouse (self) HSP-60, or a combination of the two demonstrated that T-cell proliferation in response to self-HSP-60 was only observed after immunization with both HSP-60s. A shift in cytokine secretion following in vitro stimulation was also observed, changing from anti-inflammatory IL-10 secretion when immunized with self-HSP-60 to pro-inflammatory IFN-γ when immunized with both.59 This suggests that a chlamydial infection can induce autoimmunity, and this is supported by recent findings that human HSP-60 and cHSP-60-1 from C. trachomatis serovar D contain four potential T-cell epitopes that display 100% identity.59,60 There is still some doubt over how involved cHSP-60 is in the development of autoimmunity, as, in these same experiments, immunization of mice with cHSP-60 alone did not induce cross-reactive autoimmune T cells;59 however, during an actual chlamydial infection, it is highly likely that both host and chlamydial HSP-60 are produced.

The earlier studies highlights that it is not necessarily the damage caused by the infection itself that leads to the development of reproductive sequelae such as PID, but rather the host’s immune response to infection that may actually cause the damage.

Treatment or Prevention?

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chlamydia infection and immunity
  5. Treatment or Prevention?
  6. Problems with Vaccine Development
  7. Conclusions
  8. Acknowledgments
  9. References

The current recommended treatments for genital tract infections caused by C. trachomatis are azithromycin or doxycycline.61 Azithromycin is considered more effective because of it being a single 1-g dose compared to a 7-day course of doxycycline, thereby enhancing compliance.61 There is emerging evidence that C. trachomatis is developing antibiotic resistance, with some clinical isolates having single and multidrug resistance when cultured in vitro.62–65 Isolates have been individually resistant to tetracyclines, macrolides, fluoroquinolones,64 or resistant to doxycycline, azithromycin, and ofloxacin.65 In addition, a study of infected women, who completed antibiotic treatment, found that 10% of the cohort was re-infected within 1 month of treatment completion, and 13% by 3 months, even though abstinence or 100% condom use was reported.66 While the shortened duration of infections from early antibiotic treatment has reduced infection-associated reproductive sequelae, the number of case rates continues to increase.67 This has been suggested to occur, because early intervention with antibiotics interferes with the development of protective immune responses,33 thereby increasing the risk of re-infection, and this has been termed the arrested immunity hypothesis.67

In light of the increasing rates of C. trachomatis genital infections, the asymptomatic nature of infections, and the possibility of antibiotic resistance developing, there is an urgent need for the development of a vaccine that protects both from infection and from the development of pathology. Mathematical modeling has suggested that even a partially protective vaccine will dramatically decrease the rate of spread of infections and reduce economic burden.68, 69 An efficacious vaccine will need to induce both a strong Th1-cell-mediated response and a humoral response.70Chlamydia vaccine research has been ongoing for over 20 years, exploring the efficacy of subunit, cellular, and DNA vaccines,70, 71 with many advances occurring, but as yet, no fully protective vaccine exists.

The greatest amount of Chlamydia vaccine research to date has focused on subunit vaccines. The use of the major outer membrane protein (MOMP) as a vaccine candidate has been extensively studied, with varying success.72–79 The use of this antigen has resulted from the fact that it constitutes approximately 60% of the outer membrane protein mass of the chlamydial EB.47 However, MOMP contains four variable domains that are surface exposed and are antigenically variable between serovars.80 This means any vaccine utilizing MOMP as the main antigen will elicit only serovar-specific immunity, which is not appropriate considering there are nine genital serovars (D-L) alone. This highlights that a vaccine containing only MOMP is unlikely to be successful; however, MOMP could be used as part of a multisubunit vaccine. However, our recent studies on the serovar distribution of C. trachomatis infections in regional New South Wales suggest that a MOMP-based vaccine containing MOMP from serovars E, F, and G could potentially protect against >80% of infections in this region.81

The vaccine candidate currently at the forefront of current chlamydial vaccine research is chlamydial protease-like activity factor (CPAF) and is possibly the candidate closest to human clinical trials. CPAF has been extensively studied in the murine model of genital infection82–87 and has proven, with the use of adjuvants such as IL-12 and CpG-ODN,82, 85 to be able to reduce the level of Chlamydia shed from the genital tract and prevent the development of pathology, thereby preserving reproductive health.82, 84–86, 88 Due to CPAF being highly conserved between chlamydial species89 and the fact that transgenic mice expressing human leukocyte antigen-DR4 molecules, rather than mouse major histocompatibility complex class II molecules, are able to mount robust protective immune responses,87 this suggests CPAF could be a good candidate for an efficacious vaccine, especially when used in combination with other protective antigens.

Any chlamydial vaccine candidate needs to be able to not only protect the individual from infection but also prevent the development of pathological sequelae such as infertility. This requires a vaccine to induce CD4+ T-cell-mediated immunity, along with neutralizing antibodies and importantly long lasting immunity. As yet, no single candidate is able to do this effectively and will likely require the development of a multi-subunit vaccine.

Problems with Vaccine Development

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chlamydia infection and immunity
  5. Treatment or Prevention?
  6. Problems with Vaccine Development
  7. Conclusions
  8. Acknowledgments
  9. References

The advancement of molecular techniques and availability of immunologically defined animals has allowed the development of vaccine candidates and identified the likely mechanisms of protection. However, there are still many unresolved issues, including how efficacious does a vaccine have to be to prevent further spread and pathology development? As mentioned previously, mathematical modeling has indicated that even a partially protective vaccine will significantly reduce the health care burden;68, 69 however, in light of the ability of cytokines secreted from non-immune cells to cause significant reproductive tract tissue destruction, even a low level infection has the potential to cause damage.90 This suggests that a vaccine designed to prevent pathology development rather than infection may be more cost effective.

There are very few studies that have examined the effects of the timing of vaccination. For example, it is unknown whether any candidate vaccines have a therapeutic effect, or whether immunization after a previously resolved infection will provide additional protection against re-exposure. Very early studies in humans indicated that individuals that had had previous ocular infections who were then immunized with a killed whole cell vaccine developed enhanced pathology of the eye upon re-exposure, compared to those who were not immunized.91 This occurrence was thought to be linked to the high homology seen between cHSP-60 and self-HSP-60, contributing to autoimmunity and pathology development. Because of this, investigations using whole cell vaccines were not continued. This highlights the need to select vaccine antigens that elicit protective immunity but do not enhance pathology, particularly in individuals who might have an asymptomatic infection at the time of vaccination, or who may have had an infection prior to vaccination.

There have been no studies that have examined the effects of vaccine administration during an acute chlamydial genital infection. Therefore, it is unknown whether any experimental chlamydial vaccine candidates could have a therapeutic effect, whether they might reduce or enhance pathological sequelae, or whether they could cause chronic, persistent infections, when administered during an infection. Knowing that Chlamydia can enter a persistent state when put under various pressures, including cytokine production,92–105 it is plausible that enhancement of infection-induced immune responses by vaccination may cause the Chlamydia to enter this state and promote both pathology development and future reactivation of infection. It is also unknown whether any vaccine candidates administered after resolution of a previous genital infection will further boost the individual’s infection-induced immune response, provide a greater level of protection and prevent further pathology development. Herpes simplex virus-2 (HSV-2) vaccine trials in women revealed that those who were HSV-1 seropositive at the time of vaccination did not mount an effective immune response. However, women who were seronegative for HSV-1 and 2 mounted strong anti-HSV-2 immune responses.106 With genital tract Chlamydia infection rates on the continual rise and the asymptomatic nature of infections, these are important aspects that have yet to be examined in any way.

A vaccine designed to target the mucosal surfaces of the female reproductive tract could also be affected by reproductive cycle-associated changes in female sex hormones.107 Studies on animal models have shown that progesterone and estradiol can affect many components of the immune response, including antigen presentation by DCs and macrophages,108 production and transport of antibody into the female reproductive tract (FRT)109,110 and also the induction of cell-mediated immunity.111–113 The stage of the hormonal cycle has also been shown to influence the effectiveness of vaccination. The ability of transcutaneous and intranasal vaccination to induce immune responses in the FRT of mice is hormonally regulated,114 with degree of antigen-specific T-cell stimulation and local antibody secretion dependent on the stage of estrous when vaccination occurs.114 A study in women, examining the effect of the route of vaccination and how the stage of the menstrual cycle affects antibody secretions in the reproductive tract, demonstrated that immunization via the nasal route induced the greatest IgA antibody secretion in vaginal secretions. However, those immunized vaginally on days 10 and 24 of their menstrual cycle had the greatest amounts of IgG and IgA in cervical secretions, compared to those immunized vaginally irrespective of cycle stage.115 With these factors in mind, any vaccine targeted to the female reproductive tract must induce a strong CMI and humoral response that is able to overcome the effects of hormonal fluctuations.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Chlamydia infection and immunity
  5. Treatment or Prevention?
  6. Problems with Vaccine Development
  7. Conclusions
  8. Acknowledgments
  9. References

Chlamydia trachomatis genital infections are continually increasing, with women at the greatest risk of infection and inflammatory sequelae. Because of the asymptomatic nature of most infections, the increased incidence of development of severe reproductive impairment with re-infection and the fact that antibiotic treatment has been unable to halt the increased incidence of infection, there is an urgent need for the development of a vaccine that prevents further spread of infection and pathological damage to the female reproductive tract. Factors that should be considered when developing any potential vaccine include targeting the protective immune response to the reproductive tract, the infection status of vaccines, and potentially the influence of hormonal status on protection.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Chlamydia infection and immunity
  5. Treatment or Prevention?
  6. Problems with Vaccine Development
  7. Conclusions
  8. Acknowledgments
  9. References

AC is supported by an Australian National Health & Medical Research Council Postgraduate Training Scholarship. KB is supported by grants from the National Health & Medical Research Council and the Australian Research Council.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Chlamydia infection and immunity
  5. Treatment or Prevention?
  6. Problems with Vaccine Development
  7. Conclusions
  8. Acknowledgments
  9. References
  • 1
    Beagley K, Timms P: Chlamydial trachomatis infection: incidence, health costs and prospects for vaccine development. J Reprod Immunol 2000; 48:4768.
  • 2
    Cohen C, Brunham R: Pathogenesis of Chlamydia induced pelvic inflammatory disease. Sex Transm Infect 1999; 75:2124.
  • 3
    Mardh P-A: Tubal factor infertility, with special regard to chlamydial salpingitis. Curr Opin Infect Dis 2004; 17:4952.
  • 4
    Gonzales G, Munoz C, Suchez R, Henkel R, Gallegos-Avila G, Diaz-Gutierrez O, Vill P, Kortebani G, Mazzolli A, Bustos-Obregon E: Update on the impact of Chlamydia trachomatis infection on male fertility. Andrologia 2004; 36:123.
  • 5
    Hillis SD, Owens LM, Marchbanks PA, Amsterdam LF, Mac Kenzie WR: Recurrent chlamydial infections increase the risks of hospitalization for ectopic pregnancy and pelvic inflammatory disease. Am J Obstet Gynecol 1997; 176:103107.
  • 6
    Eng T, Butler W: Confronting Sexually Transmitted Diseases: The Hidden Epidemic. Washington DC, National Academy Press, 1997.
  • 7
    CDC: Centres for Disease Control and Prevention. Sexually Transmitted Disease Surveillance. Atlanta, GA, Department of Health and Human Services, 2007.
  • 8
    Brunham RC, Rekart ML: Considerations on Chlamydia trachomatis disease expression. FEMS Immunol Med Microbiol 2009; 55:162166.
  • 9
    Fine D, Dicker L, Mosure D, Berman S: Increasing Chlamydia positivity in women screened in family planning clinics: do we know why? Sex Transm Dis 2008; 35:4752.
  • 10
    Walleser S, Salkeld G, Donovan B: The cost effectiveness of screening for genital Chlamydia trachomatis infection in Australia. Sex Health 2006; 3:225234.
  • 11
    Honey E, Augood C, Templeton A, Russell I, Paavonen J, Mardh P-A, Stary A, Stray-Pedersen B: Cost effectiveness of screening for Chlamydia trachomatis: a review of published studies. Sex Transm Infect 2002; 78:406412.
  • 12
    Brunham RC, Rey-Ladino J: Immunology of Chlamydia infection: implications for a Chlamydia trachomatis vaccine. Nat Rev Immunol 2005; 5:149161.
  • 13
    Cunningham KA, Beagley KW: Male genital tract chlamydial infection: implications for pathology and infertility. Biol Reprod 2008; 79:180189.
  • 14
    Krause W, Bohring C: Male infertility and genital chlamydial infection: victim or perpetrator? Andrologia 2003; 35:209216.
  • 15
    Vigil P, Morales P, Tapia A, Riquelme R, Salgado A: Chlamydia trachomatis infection in male partners of infertile couples: incidence and sperm function. Andrologia 2002; 34:155161.
  • 16
    Zervomanolakis I, Ott W, Hadziomerovic D, Mattle V, Seeber B, Virgolini I, Heute D, Kissler S, Leyendecker G, Wildt L: Physiology of upward transport in the human female genital tract. Ann NY Acad Sci 2007; 1101:120.
  • 17
    Kadanali S, Varoglu E, Komec D, Uslu H: Evaluation of active and passive transport mechanisms in genital tracts of IUD-bearing women with radionuclide hysterosalpingoscintigraphy. Contraception 2001; 63:4145.
  • 18
    Stagg AJ, Tuffrey M, Woods C, Wunderink E, Knight SC: Protection against ascending infection of the genital tract by Chlamydia trachomatis is associated with recruitment of major histocompatibility complex class II antigen-presenting cells into uterine tissue. Infect Immun 1998; 66:35353544.
  • 19
    Morrison SG, Morrison RP: In situ analysis of the evolution of the primary immune response in murine Chlamydia trachomatis genital tract infection. Infect Immun 2000; 68:28702879.
  • 20
    Rank RG, Bowlin AK, Kelly KA: Characterization of lymphocyte response in the female genital tract during ascending chlamydial genital infection in the guinea pig model. Infect Immun 2000; 68:52935298.
  • 21
    Kelly KA, Walker JC, Jameel SH, Gray HL, Rank RG: Differential regulation of CD4 lymphocyte recruitment between the upper and lower regions of the genital tract during Chlamydia trachomatis infection. Infect Immun 2000; 68:15191528.
  • 22
    Kelly K, Rank R: Identification of homing receptors that mediate the recruitment of CD4 T cells to the genital tract following intravaginal infection with Chlamydia trachomatis. Infect Immun 1997; 65:51985208.
  • 23
    Maxion HK, Kelly KA: Chemokine expression patterns differ within anatomically distinct regions of the genital tract during Chlamydia trachomatis infection. Infect Immun 2002; 70:15381546.
  • 24
    Carey AJ, Cunningham KA, Hafner LM, Timms P, Beagley KW: Effects of inoculating dose on the kinetics of Chlamydia muridarum genital infection in female mice. Immunol Cell Biol 2009; 87:337343.
  • 25
    Darville T, Andrews C Jr, Laffoon K, Shymasani W, Kishen L, Rank R: Mouse strain-dependent variation in the course and outcome of chlamydial genital tract infection is associated with differences in host response. Infect Immun 1997; 65:30653073.
  • 26
    Maxion HK, Liu W, Chang M-H, Kelly KA: The infecting dose of Chlamydia muridarum modulates the innate immune response and ascending infection. Infect Immun 2004; 72:63306340.
  • 27
    Cotter T, Miranpuri G, Ramsey K, Poulsen C, Byrne G: Reactivation of chlamydial genital tract infection in mice. Infect Immun 1997; 65:20672073.
  • 28
    Rank RG, Bowlin AK, Reed RL, Darville T: Characterization of chlamydial genital infection resulting from sexual transmission from male to female guinea pigs and determination of infectious dose. Infect Immun 2003; 71:61486154.
  • 29
    Kelly K: Cellular immunity and Chlamydia genital infection: induction, recruitment, and effector mechanisms. Int Rev Immunol 2003; 22:241.
  • 30
    Brunham RC, Kimani J, Bwayo J, Maitha G, Maclean I, Yang C, Shen C, Roman S, Nagelkerke NJ, Cheang M, Plummer FA: The epidemiology of Chlamydia trachomatis within a sexually transmitted diseases core group. J Infect Dis 1996; 173:950956.
  • 31
    Witkin SS, Linhares I, Giraldo P, Jeremias J, Ledger WJ: Individual immunity and susceptibility to female genital tract infection. Am J Obstet Gynecol 2000; 183:252256.
  • 32
    Golden MR, Schillinger JA, Markowitz L, St Louis ME: Duration of untreated genital infections with Chlamydia trachomatis: a review of the literature. Sex Transm Dis 2000; 27:329337.
  • 33
    Brunham RC, Pourbohloul B, Mak S, White R, Rekart ML: The unexpected impact of a Chlamydia trachomatis infection control program on susceptibility to reinfection. J Infect Dis 2005; 192:18361844.
  • 34
    Su H, Caldwell H: CD4+ T cells play a significant role in adoptive immunity to Chlamydia trachomatis infection of the mouse genital tract. Infect Immun 1995; 63:33023308.
  • 35
    Morrison SG, Morrison RP: A predominant role for antibody in acquired immunity to chlamydial genital tract reinfection. J Immunol 2005; 175:75367542.
  • 36
    Igietseme JU, Magee DM, Williams DM, Rank RG: Role for CD8+ T cells in antichlamydial immunity defined by Chlamydia-specific T-lymphocyte clones. Infect Immun 1994; 62:51955197.
  • 37
    Agrawal T, Vats V, Salhan S, Mittal A: The mucosal immune response to Chlamydia trachomatis infection of the reproductive tract in women. J Reprod Immunol 2009; 4:4.
  • 38
    Barteneva N, Theodor I, Peterson E, De La Maza L: Role of neutrophils in controlling early stages of a Chlamydia trachomatis infection. Infect Immun 1996; 64:48304833.
  • 39
    Zhang D, Yang X, Lu H, Zhong G, Brunham RC: Immunity to Chlamydia trachomatis mouse pneumonitis induced by vaccination with live organisms correlates with early granulocyte-macrophage colony-stimulating factor and interleukin-12 production and with dendritic cell-like maturation. Infect Immun 1999; 67:16061613.
  • 40
    Ficarra M, Ibana JS, Poretta C, Ma L, Myers L, Taylor SN, Greene S, Smith B, Hagensee M, Martin DH, Quayle AJ: A distinct cellular profile is seen in the human endocervix during Chlamydia trachomatis infection. Am J Reprod Immunol 2008; 60:415425.
  • 41
    Agrawal T, Vats V, Wallace PK, Singh A, Salhan S, Mittal A: Recruitment of myeloid and plasmacytoid dendritic cells in cervical mucosa during Chlamydia trachomatis infection. Clin Microbiol Infect 2009; 15:5059.
  • 42
    Hvid M, Baczynska A, Deleuran B, Fedder J, Knudsen HJ, Christiansen G, Birkelund S: Interleukin-1 is the initiator of fallopian tube destruction during Chlamydia trachomatis infection. Cell Microbiol 2007; 9:27952803.
  • 43
    Rasmussen SJ, Eckmann L, Quayle AJ, Shen L, Zhang Y-X, Anderson DJ, Fierer J, Stephens RS, Kagnoff MF: Secretion of proinflammatory cytokines by epithelial cells in response to Chlamydia infection suggests a central role for epithelial cells in chlamydial pathogenesis. J Clin Invest 1997; 99:7787.
  • 44
    Tseng C-TK, Rank RG: Role of NK cells in early host response to chlamydial genital infection. Infect Immun 1998; 66:58675875.
  • 45
    Stephens RS: The cellular paradigm of chlamydial pathogenesis. Trends Microbiol 2003; 11:4451.
  • 46
    Darville T, O’Neill JM, Andrews CW Jr, Nagarajan UM, Stahl L, Ojcius DM: Toll-like receptor-2, but not toll-like receptor-4, is essential for development of oviduct pathology in chlamydial genital tract infection. J Immunol 2003; 171:61876197.
  • 47
    Brunham RC, Peeling RW: Chlamydia trachomatis antigens: role in immunity and pathogenesis. Infect Agents Dis 1994; 3:218233.
  • 48
    Kinnunen A, Paavonen J, Surcel HM: Heat shock protein 60 specific T-cell response in chlamydial infections. Scand J Immunol 2001; 54:7681.
  • 49
    Patton DL, Sweeney YT, Kuo CC: Demonstration of delayed hypersensitivity in Chlamydia trachomatis salpingitis in monkeys: a pathogenic mechanism of tubal damage. J Infect Dis 1994; 169:680683.
  • 50
    Watkins NG, Hadlow WJ, Moos AB, Caldwell HD: Ocular delayed hypersensitivity: a pathogenetic mechanism of chlamydial-conjunctivitis in guinea pigs. Proc Natl Acad Sci USA 1986; 83:74807484.
  • 51
    Taylor H, Johnson S, Schachter J, Caldwell H, Prendergast R: Pathogenesis of trachoma: the stimulus for inflammation. J Immunol 1987; 138:30233027.
  • 52
    Kinnunen A, Molander P, Laurila A, Rantala I, Morrison R, Lehtinen M, Karttunen R, Tiitinen A, Paavonen J, Surcel H-M: Chlamydia trachomatis reactive T lymphocytes from upper genital tract tissue specimens. Hum Reprod 2000; 15:14841489.
  • 53
    Lichtenwalner AB, Patton DL, Van Voorhis WC, Sweeney YTC, Kuo C-C: Heat shock protein 60 is the major antigen which stimulates delayed-type hypersensitivity reaction in the macaque model of Chlamydia trachomatis Salpingitis. Infect Immun 2004; 72:11591161.
  • 54
    Peeling RW, Kimani J, Plummer F, Maclean I, Cheang M, Bwayo J, Brunham RC: Antibody to chlamydial hsp60 predicts an increased risk for chlamydial pelvic inflammatory disease. J Infect Dis 1997; 175:11531158.
  • 55
    Peeling RW, Patton DL, Cosgrove Sweeney YT, Cheang MS, Lichtenwalner AB, Brunham RC, Stamm WE: Antibody response to the chlamydial heat-shock protein 60 in an experimental model of chronic pelvic inflammatory disease in monkeys (Macaca nemestrina). J Infect Dis 1999; 180:774779.
  • 56
    Eckert LO, Hawes SE, Wolner-Hanssen P, Money DM, Peeling RW, Brunham RC, Stevens CE, Eschenbach DA, Stamm WE: Prevalence and correlates of antibody to chlamydial heat shock protein in women attending sexually transmitted disease clinics and women with confirmed pelvic inflammatory disease. J Infect Dis 1997; 175:14531458.
  • 57
    Ault KA, Statland BD, King MM, Dozier DI, Joachims ML, Gunter J: Antibodies to the chlamydial 60 kilodalton heat shock protein in women with tubal factor infertility. Infect Dis Obstet Gynecol 1998; 6:163167.
  • 58
    Zhao H, Li H: Immunohistochemical analysis of TNF-alpha and HSP-60 in women with tubal factor infertility associated with Chlamydia trachomatis. J Huazhong Univ Sci Technolog Med Sci 2004; 24:630632.
  • 59
    Yi Y, Yang X, Brunham RC: Autoimmunity to heat shock protein 60 and antigen-specific production of interleukin-10. Infect Immun 1997; 65:16691674.
  • 60
    Campanella C, Marino Gammazza A, Mularoni L, Cappello F, Zummo G, Di Felice V: A comparative analysis of the products of GROEL-1 gene from Chlamydia trachomatis serovar D and the HSP60 var1 transcript from Homo sapiens suggests a possible autoimmune response. Int J Immunogenet 2009; 36:7378.
  • 61
    Adimora Adaora A: Treatment of uncomplicated genital Chlamydia trachomatis infections in adults. Clin Infect Dis 2002; 35:S183S186.
  • 62
    Horner P: The case for further treatment studies of uncomplicated genital Chlamydia trachomatis infection. Sex Transm Infect 2006; 82:340343.
  • 63
    Jones RB, Van der Pol B, Martin DH, Shepard MK: Partial characterization of Chlamydia trachomatis isolates resistant to multiple antibiotics. J Infect Dis 1990; 162:13091315.
  • 64
    Rice RJ, Bhullar V, Mitchell SH, Bullard J, Knapp JS: Susceptibilities of Chlamydia trachomatis isolates causing uncomplicated female genital tract infections and pelvic inflammatory disease. Antimicrob Agents Chemother 1995; 39:760762.
  • 65
    Somani J, Bhullar VB, Workowski KA, Farshy CE, Black CM: Multiple drug-resistant Chlamydia trachomatis associated with clinical treatment failure. J Infect Dis 2000; 181:14211427.
  • 66
    Katz B, Fortenberry D, Orr D: Factors affecting chlamydial persistence or recurrence one and three months after treatment. In Chlamydia Infections: Proceedings of the Ninth International Symposium on Human Chlamydial Infections, RSStephens, GChristiansen, ByrneGl, ClarkeLN, GraystonJT, RankRG, RidgwayGL, SaikkuP, SchachterJ, StammWE (ed). Napa, CA, Berkeley, CA, Berkeley University Press, 1998, pp 3538.
  • 67
    Brunham RC, Rekart ML: The arrested immunity hypothesis and the epidemiology of Chlamydia control. Sex Transm Dis 2008; 35:5354.
  • 68
    De La Maza MA, De La Maza LM: A new computer model for estimating the impact of vaccination protocols and its application to the study of Chlamydia trachomatis genital infections. Vaccine 1995; 13:119127.
  • 69
    Gray Richard T, Beagley Kenneth W, Timms P, Wilson David P: Modeling the impact of potential vaccines on epidemics of sexually transmitted Chlamydia trachomatis infection. J Infect Dis 2009; 199:16801688.
  • 70
    Hafner LM, McNeilly C: Vaccines for Chlamydia infections of the female genital tract. Future Microbiol 2008; 3:6777.
  • 71
    Hafner L, Beagley K, Timms P: Chlamydia trachomatis infection: host immune responses and potential vaccines. Mucosal Immunol 2008; 1:116130.
  • 72
    Berry LJ, Hickey DK, Skelding KA, Bao S, Rendina AM, Hansbro PM, Gockel CM, Beagley KW: Transcutaneous immunization with combined cholera toxin and CpG adjuvant protects against Chlamydia muridarum genital tract infection. Infect Immun 2004; 72:10191028.
  • 73
    Cheng C, Bettahi I, Cruz-Fisher MI, Pal S, Jain P, Jia Z, Holmgren J, Harandi AM, De La Maza LM: Induction of protective immunity by vaccination against Chlamydia trachomatis using the major outer membrane protein adjuvanted with CpG oligodeoxynucleotide coupled to the nontoxic B subunit of cholera toxin. Vaccine 2009; 15:15.
  • 74
    Cunningham KA, Carey AJ, Lycke N, Timms P, Beagley KW: CTA1-DD is an effective adjuvant for targeting anti-chlamydial immunity to the murine genital mucosa. J Reprod Immunol 2009; 81:3438.
  • 75
    Igietseme JU, Murdin A: Induction of protective immunity against Chlamydia trachomatis genital infection by a vaccine based on major outer membrane protein-lipophilic immune response-stimulating complexes. Infect Immun 2000; 68:67986806.
  • 76
    Pal S, Davis HL, Peterson EM, De La Maza LM: Immunization with the Chlamydia trachomatis mouse pneumonitis major outer membrane protein by use of CpG oligodeoxynucleotides as an adjuvant induces a protective immune response against an intranasal chlamydial challenge. Infect Immun 2002; 70:48124817.
  • 77
    Pal S, Peterson EM, Rappuoli R, Ratti G, De La Maza LM: Immunization with the Chlamydia trachomatis major outer membrane protein, using adjuvants developed for human vaccines, can induce partial protection in a mouse model against a genital challenge. Vaccine 2006; 24:766775.
  • 78
    Pal S, Theodor I, Peterson EM, De La Maza LM: Immunization with the Chlamydia trachomatis mouse pneumonitis major outer membrane protein can elicit a protective immune response against a genital challenge. Infect Immun 2001; 69:62406247.
  • 79
    Singh SR, Hulett K, Pillai SR, Dennis VA, Oh MK, Scissum-Gunn K: Mucosal immunization with recombinant MOMP genetically linked with modified cholera toxin confers protection against Chlamydia trachomatis infection. Vaccine 2006; 24:12131224.
  • 80
    Stephens RS, Sanchez-Pescador R, Wagar EA, Inouye C, Urdea MS: Diversity of Chlamydia trachomatis major outer membrane protein genes. J Bacteriol 1987; 169:38793885.
  • 81
    Mossman D, Beagley KW, Landay AL, Loewenthal M, Ooi C, Timms P, Boyle M: Genotyping of urogenital Chlamydia trachomatis in regional New South Wales, Australia. Sex Transm Dis 2008; 35:614616.
  • 82
    Cong Y, Jupelli M, Guentzel MN, Zhong G, Murthy AK, Arulanandam BP: Intranasal immunization with chlamydial protease-like activity factor and CpG deoxynucleotides enhances protective immunity against genital Chlamydia muridarum infection. Vaccine 2007; 25:37733780.
  • 83
    Li W, Guentzel MN, Seshu J, Zhong G, Murthy AK, Arulanandam BP: Induction of cross-serovar protection against genital chlamydial infection by a targeted multisubunit vaccination approach. Clin Vaccine Immunol 2007; 14:15371544.
  • 84
    Li W, Murthy AK, Guentzel MN, Seshu J, Forsthuber TG, Zhong G, Arulanandam BP: Antigen-specific CD4+ T cells produce sufficient IFN-{gamma} to mediate robust protective immunity against genital Chlamydia muridarum infection. J Immunol 2008; 180:33753382.
  • 85
    Murphey C, Murthy AK, Meier PA, Neal Guentzel M, Zhong G, Arulanandam BP: The protective efficacy of chlamydial protease-like activity factor vaccination is dependent upon CD4+ T cells. Cell Immunol 2006; 242:110117.
  • 86
    Murthy AK, Chambers JP, Meier PA, Zhong G, Arulanandam BP: Intranasal vaccination with a secreted chlamydial protein enhances resolution of genital Chlamydia muridarum infection, protects against oviduct pathology, and is highly dependent upon endogenous gamma interferon production. Infect Immun 2007; 75:666676.
  • 87
    Murthy AK, Cong Y, Murphey C, Guentzel MN, Forsthuber TG, Zhong G, Arulanandam BP: Chlamydial protease-like activity factor induces protective immunity against genital chlamydial infection in transgenic mice that express the human HLA-DR4 allele. Infect Immun 2006; 74:67226729.
  • 88
    Murthy AK, Guentzel MN, Zhong G, Arulanandam BP: Chlamydial protease-like activity factor – insights into immunity and vaccine development. J Reprod Immunol 2009; 83:179184.
  • 89
    Dong F, Zhong Y, Arulanandam B, Zhong G: Production of a proteolytically active protein, chlamydial protease/proteasome-like activity factor, by five different Chlamydia species. Infect Immun 2005; 73:18681872.
  • 90
    Schachter J: Infection and disease epidemiology. In Chlamydia: Intracellular Biology, Pathogenesis & Immunity, RSStephens (ed). Washington DC, American Society for Microbiology, 1999, pp 150196.
  • 91
    Grayston JT, Wang S-P, Yang Y-F, Woolridge RL: The effect of trachoma virus vaccine on the course of experimental trachoma infection in blind human volunteers. J Exp Med 1962; 115:10091022.
  • 92
    LaRue RW, Dill BD, Giles DK, Whittimore JD, Raulston JE: Chlamydial Hsp60-2 Is iron responsive in Chlamydia trachomatis serovar E-infected human endometrial epithelial cells in vitro. Infect Immun 2007; 75:23742380.
  • 93
    Mukhopadhyay S, Miller RD, Sullivan ED, Theodoropoulos C, Mathews SA, Timms P, Summersgill JT: Protein expression profiles of Chlamydia pneumoniae in models of persistence versus those of heat shock stress response. Infect Immun 2006; 74:38533863.
  • 94
    Raulston J: Response of Chlamydia trachomatis serovar E to iron restriction in vitro and evidence for iron-regulated chlamydial proteins. Infect Immun 1997; 65:45394547.
  • 95
    Timms P, Good D, Wan C, Theodoropoulos C, Mukhopadhyay S, Summersgill J, Mathews S: Differential transcriptional responses between the interferon-gamma-induction and iron-limitation models of persistence for Chlamydia pneumoniae. J Microbiol Immunol Infect 2009; 42:2737.
  • 96
    Huston W, Theodoropoulos C, Mathews S, Timms P: Chlamydia trachomatis responds to heat shock, penicillin induced persistence, and IFN-gamma persistence by altering levels of the extracytoplasmic stress response protease HtrA. BMC Microbiol 2008; 8:190.
  • 97
    Kramer MJ, Gordon FB: Ultrastructural analysis of the effects of penicillin and chlortetracycline on the development of a genital tract Chlamydia. Infect Immun 1971; 3:333341.
  • 98
    Lambden PR, Pickett MA, Clarke IN: The effect of penicillin on Chlamydia trachomatis DNA replication. Microbiology 2006; 152:25732578.
  • 99
    Mpiga P, Ravaoarinoro M: Effects of sustained antibiotic bactericidal treatment on Chlamydia trachomatis-infected epithelial-like cells (HeLa) and monocyte-like cells (THP-1 and U-937). Int J Antimicrob Agents 2006; 27:316324.
  • 100
    Belland RJ, Nelson DE, Virok D, Crane DD, Hogan D, Sturdevant D, Beatty WL, Caldwell HD: Transcriptome analysis of chlamydial growth during IFN-gamma-mediated persistence and reactivation. Proc Natl Acad Sci USA 2003; 100:1597115976.
  • 101
    Goellner S, Schubert E, Liebler-Tenorio E, Hotzel H, Saluz HP, Sachse K: Transcriptional response patterns of Chlamydophila psittaci in different in vitro models of persistent infection. Infect Immun 2006; 74:48014808.
  • 102
    Kane CD, Byrne GI: Differential effects of gamma interferon on Chlamydia trachomatis growth in polarized and nonpolarized human epithelial cells in culture. Infect Immun 1998; 66:23492351.
  • 103
    Pantoja LG, Miller RD, Ramirez JA, Molestina RE, Summersgill JT: Characterization of Chlamydia pneumoniae persistence in HEp-2 cells treated with gamma interferon. Infect Immun 2001; 69:79277932.
  • 104
    Deka S, Vanover J, Dessus-Babus S, Whittimore J, Howett MK, Wyrick PB, Schoborg RV: Chlamydia trachomatis enters a viable but non-cultivable (persistent) state within herpes simplex virus type 2 (HSV-2) co-infected host cells. Cell Microbiol 2006; 8:149162.
  • 105
    Deka S, Vanover J, Sun J, Kintner J, Whittimore J, Schoborg RV: An early event in the herpes simplex virus type-2 replication cycle is sufficient to induce Chlamydia trachomatis persistence. Cell Microbiol 2007; 9:725737.
  • 106
    Stanberry LR, Spruance SL, Cunningham AL, Bernstein DI, Mindel A, Sacks S, Tyring S, Aoki FY, Slaoui M, Denis M, Vandepapeliere P, Dubin G: Glycoprotein-D-adjuvant vaccine to prevent genital herpes. N Engl J Med 2002; 347:16521661.
  • 107
    Kutteh WH, Mestecky J, Wira CR: Mucosal immunity in the human female reproductive tract. In Mucosal Immunology, JMestecky, JBienenstock, MLamm, LMayer, JRMcGhee, WStrober (eds). Burlington, MA, USA, Elsevier Academic Press, 2005, pp 16311646.
  • 108
    Beagley KW, Gockel CM: Regulation of innate and adaptive immunity by the female sex hormones oestradiol and progesterone. FEMS Immunol Med Microbiol 2003; 38:1322.
  • 109
    Sullivan DA, Wira CR: Variations in free secretory component levels in mucosal secretions of the rat. J Immunol 1983; 130:13301335.
  • 110
    Wira CR, Sandoe CP: Hormonal regulation of immunoglobulins: influence of estradiol on immunoglobulins A and G in the rat uterus. Endocrinology 1980; 106:10201026.
  • 111
    Seavey MM, Mosmann TR: Paternal antigen-bearing cells transferred during insemination do not stimulate anti-paternal CD8+ T cells: role of estradiol in locally inhibiting CD8+ T cell responses. J Immunol 2006; 177:75677578.
  • 112
    Wira CR, Rossoll RM: Antigen-presenting cells in the female reproductive tract: influence of sex hormones on antigen presentation in the vagina. Immunology 1995; 84:505508.
  • 113
    Wira CR, Rossoll RM, Kaushic C: Antigen-presenting cells in the female reproductive tract: influence of estradiol on antigen presentation by vaginal cells. Endocrinology 2000; 141:28772885.
  • 114
    Gockel CM, Bao S, Holland MK, Beagley KW: Influence of the murine oestrous cycle on the induction of mucosal immunity. Am J Reprod Immunol 2003; 50:369379.
  • 115
    Johansson E-L, Wassen L, Holmgren J, Jertborn M, Rudin A: Nasal and vaginal vaccinations have differential effects on antibody responses in vaginal and cervical secretions in humans. Infect Immun 2001; 69:74817486.