Key Points
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Sexually transmitted diseases caused by Chlamydia trachomatis are an important public-health concern worldwide. Infection causes pelvic inflammatory disease (PID), fallopian-tube scarring and sequelae that include infertility and ectopic pregnancy.
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Immunity to infection with Chlamydia spp. mainly involves CD4+ T helper 1 (TH1) effector cells, which secrete interferon-γ (IFN-γ), and B cells. IFN-γ mediates depletion of tryptophan, which is required for the growth of Chlamydia spp., whereas antibodies assist in the clearance of Chlamydia spp. on secondary infection.
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The upper compartment of the female genital tract strongly responds to infection with Chlamydia spp. Infected epithelial and immune cells in this compartment secrete pro-inflammatory cytokines, which trigger immune effector functions that clear infection but can damage tissue.
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The female genital mucosa contains inductive sites that are controlled by sex hormones. Infection with C. trachomatis further induces recruitment of lymphoid cells, which enlarge the inductive sites before the initiation of an immune response to C. trachomatis.
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Persistent forms of C. trachomatis that are generated in response to low concentrations of IFN-γ are metabolically active and seem to promote continuous secretion of pro-inflammatory cytokines, a condition that might contribute to tissue scarring.
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C. trachomatis antigens, together with an appropriate adjuvant, are crucial for the formulation of a protective vaccine against infection with C. trachomatis. Expression of the C. muridarum antigens major outer-membrane protein (MOMP) and outer-membrane protein 2 (OMP2) in Vibrio chlolerae ghosts constitutes a vaccine formulation that induces TH1-type immune responses and highly protects mice against infection with Chlamydia muridarum (which has most of the same genes as C. trachomatis).
Abstract
Sexually transmitted Chlamydia trachomatis infections are a serious public-health problem. With more than 90 million new cases occurring annually, C. trachomatis is the most common cause of bacterial sexually transmitted disease worldwide. Recent progress in elucidating the immunobiology of Chlamydia muridarum infection of mice has helped to guide the interpretation of immunological findings in studies of human C. trachomatis infection and has led to the development of a common model of immunity. In this review, we describe our current understanding of the immune response to infection with Chlamydia spp. and how this information is improving the prospects for development of a vaccine against infection with C. trachomatis.
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Worldwide, an estimated 90 million sexually transmitted Chlamydia trachomatis infections occur each year1. More than two-thirds of these cases occur in the developing world, where diagnostic and treatment services are almost absent. Sub-Saharan Africa and southern and Southeast Asia have particularly high burdens of disease, with an estimated 15 million new cases occurring in Africa and 45 million new cases in southern Asia every year. The prevalence of infection in Asia might be even higher than this estimate, because a recent study in China concluded that 2.5% of people of 20–64 years of age are infected2. Similar prevalence rates (2.1%) have also been documented in a recent population-based study in Britain3. Rates are about twofold higher (4.2%) among a random sample of young adults (18–26 years) in the United States, highlighting a universal epidemiological feature of C. trachomatis — that infection is mainly observed in adolescents and young adults4.
Sexually transmitted C. trachomatis infection is an important public-health concern because of its adverse effects on reproduction1. In women, infection with C. trachomatis causes PELVIC INFLAMMATORY DISEASE (PID) and has long-term consequences — such as infertility, ECTOPIC PREGNANCY and chronic pelvic pain — that are secondary to scarring of the fallopian tubes (caused by SALPINGITIS) and ovaries. In addition, infection with C. trachomatis facilitates the transmission of HIV5 and might be a co-factor in human papilloma virus (HPV)-induced cervical neoplasia6. Because of public-health concerns, programmes to control C. trachomatis have been implemented in many developed countries; these involve the detection of infected individuals through diagnostic testing, which is followed by antimicrobial treatment and tracing of individuals who might have been exposed through sexual contact with the infected person. Although these programmes might control C. trachomatis infection, many regions are now showing an increase in the number of infected individuals7. This increase might reflect, in part, improvements in diagnostic testing and/or changes in sexual behaviour. Alternatively, the administration of antimicrobial agents might be altering the development of natural immunity to C. trachomatis in the population. For example, antimicrobial agents have clearly been shown to blunt the development of immunity to Chlamydia muridarum in mouse models of infection8. Antimicrobial treatment of infected individuals helps to reduce transmission by shortening the average duration of infection. In the absence of antimicrobial therapy, C. trachomatis infections typically last for many months, but they can undergo spontaneous clearance9,10,11, which is associated with increasing age and duration of infection and is presumed to be immune mediated9,12.
Why C. trachomatis infections take so long to clear is not certain, but it might be a consequence of the many immune-evasion strategies of the organism (Box 1). Data from animal models of infection indicate that clearance depends on the recruitment of effector T cells and their clonal expansion to a crucial threshold in the genital tract13, and it might be that reaching this threshold takes many months in humans. Taken together, these observations indicate that, by shortening the average duration of infection, control programmes that involve antimicrobial treatment might be blunting the development of immunity to C. trachomatis and thereby increasing the susceptibility of the population to C. trachomatis transmission.
This hypothesis for why the rates of infection with C. trachomatis increase in the face of control programmes needs to be validated, but if it is correct, it has obvious implications for the need for a vaccine to adequately control this infectious disease. Because C. trachomatis is such an important pathogen from a public-health perspective and because current programmes for the control of C. trachomatis infection are not affordable for much of the developing world and might have an inherent weakness, vaccine development has been identified as essential to controlling infection with C. trachomatis.
In general, a vaccine against C. trachomatis needs to elicit protective T-cell and B-cell immunity in the genital-tract mucosa. Mouse models of genital infection with C. muridarum, which has most of the same genes as the human strains of C. trachomatis14, have provided information on the immune mechanisms of clearance of infection and resistance to re-infection, and these models seem to be useful for analysing immunity to C. trachomatis in humans12,15. However, there are several important differences between C. muridarum and C. trachomatis that might affect the immunobiology of infection. First, C. trachomatis infection in humans is much more prolonged than C. muridarum infection in mice: mice generally resolve infection after ∼4 weeks, whereas in humans, C. trachomatis infection can last several months before spontaneous clearance9,10,11. Second, immune-evasion strategies also differ such that some strains of C. trachomatis use tryptophan biosynthesis to escape interferon-γ (IFN-γ)-mediated defence mechanisms of the host (Box 1), whereas C. muridarum does not14,16. Last, C. trachomatis shows substantial allelic variation of its dominant surface protein — the major outer-membrane protein (MOMP) — whereas C. muridarum has a single allele14. Because MOMP seems to be an important target of immunity, the specificity of immunity to different serovars (strains) of C. trachomatis12 cannot be studied in the C. muridarum model. Although these differences limit the direct extrapolation of findings from C. muridarum infection to C. trachomatis infection, the mouse model has provided information about the immunobiology of C. trachomatis and is guiding the development of a vaccine against infection with this organism.
Here, we review the data generated from studies of C. muridarum genital-tract infection of mice and the similar observations obtained from studies of human infection with C. trachomatis that have led to our current understanding of the immunology of infection with Chlamydia spp. Understanding the immunological basis of immunity to Chlamydia spp. and identifying correlates of protective immunity will provide a rational foundation for the design of a vaccine against infection with C. trachomatis17. Because T-cell immunity is central to both mouse and human immunity to Chlamydia spp., we describe the antigens derived from C. trachomatis and C. muridarum that are important for eliciting T-cell responses. Last, we describe how these results, together with recent findings from studies of multisubunit vaccines administered to C. muridarum-infected mice, are informing the design of a vaccine against C. trachomatis for use in humans.
Infection process
C. trachomatis is an obligate intracellular bacterium that causes several sexually transmitted diseases in humans18 (Table 1). C. trachomatis normally infects the single-cell columnar layer of the epithelium in the endocervix of women (Fig. 1) and the urethra of men. Inside epithelial cells, Chlamydia spp. undergo a unique developmental cycle that produces infective forms (known as elementary bodies), which then infect neighbouring epithelial cells (Fig. 2). At the site of mucosal infection, intense inflammation that is characterized by redness, oedema and discharge can occur, resulting in the clinical syndrome of MUCOPURULENT CERVICITIS in women and NON-GONOCOCCAL URETHRITIS in men19. However, despite initiating local inflammation, C. trachomatis infection remains subclinical in a high proportion of infected individuals (70–90% of women and 30–50% of men)19. Asymptomatically infected women can show signs of disease: in general, mucopurulent endocervical discharge, HYPERTROPHIC CERVICAL ECTOPY and friability (that is, easily induced bleeding of the cervical epithelium)20. Clinical symptoms include dysuria, abnormal vaginal discharge, abnormal menstrual bleeding, postcoital bleeding and lower abdominal pain19. In some untreated women (20–40%), infection ascends the endometrial epithelium to the fallopian tubes, where C. trachomatis can establish persistent infection and cause PID. Overall, 11% of women with PID develop tubal factor infertility and 9% develop ectopic pregnancies21. Moreover, this risk seems to be higher for those with PID caused by infection with C. trachomatis compared with PID caused by other factors, such as infection with Neisseria gonorrhoeae22.
Immunobiology
Elucidating the immunobiology of infection with Chlamydia spp. is essential for developing a vaccine. A vaccine needs to induce immune responses that are protective and not responses that are associated with persistence of infection or immunopathology. Establishing immune correlates of protection facilitates the identification of protective antigens in animal models of infection and guides Phase I and Phase II trials of immunogenicity in humans. Identification of immune correlates of protection is an important priority in C. trachomatis research, and C. muridarum infection models have begun to shed light on immune correlates of protection against infection with C. trachomatis. The mouse model of vaginal infection (using C. muridarum) has been used to analyse the innate and adaptive responses to infection with C. trachomatis, and it seems to closely mimic acute infection of the genital tract in women12,15.
Cytokines. After infection with Chlamydia spp., epithelial cells produce various pro-inflammatory mediators, including CXC-chemokine ligand 1 (CXCL1), CXCL8 (also known as interleukin-8, IL-8), CXCL16, granulocyte/ monocyte colony-stimulating factor (GM-CSF), IL-1α, IL-6 and tumour-necrosis factor (TNF)23,24. Infected epithelial cells also upregulate expression of the chemokines CC-chemokine ligand 5 (CCL5) and CXCL10, and they secrete cytokines that promote the production of IFN-γ, including IFN-α, IFN-β and IL-12 (Refs 24,25). Infected fibroblasts secrete IFN-α, IFN-β and nitric oxide26, whereas infected macrophages produce TNF and IL-6 (Ref. 27). Most of these are T helper 1 (TH1)-cell cytokines, which have a role in polarizing the immune response to Chlamydia spp. towards a protective TH1-type response24. By contrast, cytokines such as TNF, IL-1α and IL-6 might be involved in the pathology associated with infection with Chlamydia spp.27 Together, these cytokines trigger inflammation and promote the recruitment of immune cells, thereby actively contributing to the development of innate and adaptive immune responses.
Toll-like receptors and dendritic cells. Toll-like receptors (TLRs) detect microbial infection and have an essential role in the induction of innate and adaptive immune responses28. A recent hypothesis states that differential expression and engagement of TLR-family members at the surface of dendritic cells (DCs) influences the type of immune response that is induced by a microbial pathogen28. Infection with C. muridarum has been shown to stimulate DCs to produce IL-12 (a cytokine that polarizes immune responses to TH1-type responses)29,30 and CXCL10 (a chemokine that recruits T cells) and to express CC-chemokine receptor 7 (CCR7; a chemokine receptor that is required for the migration of DCs to local lymph nodes)31. And, although it is not confirmed which particular TLRs expressed by DCs are engaged by Chlamydia spp., TLR2 might have an important role in the activation of DCs by Chlamydophila pneumoniae32. Furthermore, signalling through TLR2, but not TLR4, is associated with increased fallopian-tube pathology in C. muridarum-infected mice27, indicating that engagement of TLR2 is a potential common pathway in both the immunity and immunopathology induced by Chlamydia spp. Given the high level of expression of TLRs by DCs and the ability of DCs to polarize immune responses, the identification of the role of DCs in Chlamydia-specific immune responses is crucial for understanding the type of immune response that is elicited and therefore also for designing a vaccine against infection with C. trachomatis.
DCs have been found in mouse vaginal and cervical mucosae33 and are recruited to the site of inflammation in response to infection with Chlamydia spp.34 Evidence indicates that sampling of microbial antigen across the epithelia of the vagina is accomplished by migratory DCs that carry antigens to peripheral lymph nodes, where antigen is presented to naive T cells35. Mature DCs are highly effective at presenting antigen and priming protective adaptive immune responses. Accordingly, adoptive transfer of DCs pulsed with C. muridarum elementary bodies protects mice against subsequent infection29. Live and inactivated C. muridarum induce different levels of DC maturation, and adoptive transfer of DCs pulsed with live C. muridarum has been shown to be even more effective at providing protective immunity than DCs pulsed with inactivated bacteria36. These observations might help to explain why vaccination with whole inactivated C. trachomatis was only partially protective in human trials37.
Immature DCs and regulatory DCs have also been described to be associated with immune tolerance38 and therefore might have a role in promoting disease pathogenesis, although this has not yet been studied for Chlamydia spp. Studies of DCs that reside in the genital tract will be essential to enable the design of vaccines against infection with C. trachomatis.
Inductive sites. Although the female genital tract (FGT) mucosa lacks the organized lymphoid structures that are found at other mucosal sites (Box 2), such as the PEYER'S PATCHES in the intestine, after infection with Chlamydia spp., immune cells are recruited to the inflammatory site in the FGT in response to chemokines that are secreted by infected epithelial cells. This results in the subsequent accumulation of lymphocytes and other immune cells and the formation of immune inductive sites (Fig. 1), in which naive B and T cells are clonally selected and expanded39. In FGT infection with C. muridarum, these sites form perivascular lymphoid clusters that mainly contain CD4+ T cells40. In women who have a genital-tract infection with C. trachomatis, the inductive sites form lymphoid follicles that mature into germinal centres41. By contrast, in primates with trachoma — an ocular disease caused by C. trachomatis — inductive sites take the form of lymphoid follicles that contain plasma cells, B cells, T cells, DCs, macrophages and neutrophils42. Importantly, systemically circulating lymphocytes also seem to be recruited to the FGT during infection with Chlamydia spp., because the chemokines (CCL5, CCL7 and CXCL10) that attract lymphocytes are abundantly secreted by C. muridarum-infected epithelial cells24 and because the adhesion molecules MADCAM1 (mucosal vascular addressin cell-adhesion molecule 1) and VCAM1 (vascular cell-adhesion molecule 1), which are required for lymphocyte homing from mucosal and systemic inflammatory sites, are highly expressed in fallopian-tube epithelia that are infected with C. trachomatis43. So, it seems that Chlamydia-specific adaptive immune responses occur not only at mucosal immune inductive sites but also at more distant secondary lymphoid structures, such as regional lymph nodes, and immune cells at these sites then migrate to the local inflammatory site41,44,45.
CD4+ and CD8+ T cells. Studies of animal models have clearly established that T cells have a crucial role in the resolution of infection with Chlamydia spp. Accordingly, nude mice cannot control infection, and adoptive transfer of CD4+ or CD8+ Chlamydia-spp.-specific T-cell lines allows these mice to successfully control infection46,47. Specifically, protection in the C. muridarum-infection model seems to be mediated by CD4+ T cells that produce IFN-γ15,48,49, as mice deficient in MHC class II molecules50, CD4 (Refs 50,51), IL-12 (Ref. 52), IFN-γ49 or the IFN-γ receptor53 and mice depleted of C. muridarum-specific CD4+ T cells51 all have a marked inability to control infection. Furthermore, adoptive transfer of C. muridarum-specific CD4+ TH1-cell clones, but not TH2-cell clones, protected nude mice against infection with C. muridarum54.
The role and effector mechanism of Chlamydia-specific CD8+ T cells are less clear. MHC class I peptide presentation to CD8+ T cells is not essential for clearance of infection with Chlamydia spp.: mice deficient in β2-microglobulin resolved infection as efficiently as wild-type mice50,51, and mice deficient in perforin or CD95 (also known as FAS) — which are crucial cytolytic effector molecules of CD8+ T cells — effectively cleared infection with C. muridarum55, implying that CD8+ T cells are not essential for clearance of infection with Chlamydia spp. However, C. muridarum-specific CD8+ T cells efficiently lysed C. muridarum-infected cells when cells were transfected with intercellular adhesion molecule 1 (ICAM1), indicating that, in some situations, CD8+ T cells might be important for the elimination of cells infected with Chlamydia spp.56 Also, adoptive transfer of CD8+ T-cell lines specific for serovar L2 of C. trachomatis protected mice against infection with C. trachomatis through a mechanism involving production of IFN-γ57. So, CD8+ T cells might have a supporting role in limiting infection with Chlamydia spp.
Considerable in vitro and in vivo evidence shows that production of IFN-γ by C. muridarum-specific T cells is essential for clearance of C. muridarum from the genital tract15. Although the effector mechanisms of IFN-γ-mediated control of in vivo infection with C. trachomatis are not completely understood, it is well established that IFN-γ controls the in vitro growth of C. trachomatis through inducing production of the enzyme indoleamine-2,3-dioxygenase (IDO)58. Activation of IDO by IFN-γ leads to the degradation of tryptophan, and lack of this essential amino acid causes the death of C. trachomatis through tryptophan starvation58 (Fig. 3). Recently, it has been shown that genital, but not ocular, serovars of C. trachomatis can use indole as a substrate to synthesize tryptophan in the presence of IFN-γ, which might allow genital strains of C. trachomatis to escape IFN-γ-mediated eradication in the genital tract by using indole provided by the local microbial flora of the FGT16,59. Additional immune effector mechanisms that are induced by IFN-γ include the induction of nitric-oxide production, which inhibits the growth of C. muridarum60, and the promotion of TH1-type protective immune responses, which downregulate non-protective TH2-type responses49.
B cells. The importance of antibodies in immunity to C. trachomatis was indicated by an early epidemiological observation of an inverse correlation between the amount of IgA in cervical secretions and the amount of C. trachomatis recovered from the cervix of infected women61. In vitro, antibodies specific for C. trachomatis can neutralize infection in tissue culture62. However, high titres of C. trachomatis-specific antibody do not correlate with resolution of infection in humans and, in fact, are more strongly correlated with increased severity of sequelae of infection, such as tubal infertility in women63. Moreover, mice that lack B cells do not show a markedly altered course of primary genital infection with C. muridarum64. By contrast, B cells are probably important for resistance to secondary infection, because mice that have normal numbers of B cells but are depleted of CD4+ and CD8+ T cells successfully resolve secondary infection51,65. Interestingly, mice that lack Fc receptors suffer more severe secondary infection with C. muridarum than wild-type mice, owing in part to impaired cellular immune responses, which indicates that B cells and antibodies might also be important for enhancing protective effector T-cell responses66. These results indicate that, although B cells do not have a decisive role in resolution of primary infections, they might be required to control re-infection. Possible mechanisms for how B cells contribute to immunity to re-infection include antibody-mediated neutralization and opsonization, as well as enhanced antigen presentation to T cells, possibly following Fc-receptor-mediated uptake of antigen–antibody complexes51,67,68.
Overall, these data show that Chlamydia-specific CD4+ TH1 cells, and to a more limited extent CD8+ T cells and B cells, are required to control C. muridarum infection of the genital tract in mice15,69. And, observations from humans infected with C. trachomatis indicate that similar immune effector mechanisms occur in humans12,69. However, despite the mobilization of many immune effectors, infection with C. trachomatis can be recurrent and/or prolonged, which probably reflects the array of immune-evasion mechanisms of this pathogen (Box 1). Immune-avoidance mechanisms might also contribute to pathogenesis and tissue damage, by inducing persistent infection and by enhancing susceptibility to re-infection.
Models of pathogenesis
The pathogenesis of C. trachomatis disease is not completely understood, and mouse models (using infection with C. muridarum) have been less helpful in this area than they have been in elucidating the basis of immunity. Part of this discrepancy might result from the dependence of C. trachomatis pathogenesis on prolonged infection, as C. muridarum does not typically cause long-term infections.
Circumstantial evidence from studies of animals infected with Chlamydia spp. and from observations of humans infected with C. trachomatis repeatedly shows a strong correlation between Chlamydia-specific immune responses, such as antibodies and T cells specific for heat-shock protein 60 (HSP60) from Chlamydia spp., and PID and fallopian-tube pathology70,71. There are two main hypotheses of pathogenesis, and these are not mutually exclusive: first, the immunological hypothesis states that immune responses induce collateral tissue damage that is central to pathogenesis70; and second, the cellular hypothesis states that pro-inflammatory cytokines that are produced by persistently infected cells are the direct cause of tissue damage72.
The immunological hypothesis is supported by the following evidence: first, protective CD4+ TH1 cells preferentially home to the infected fallopian-tube tissue, where they can confer immunity, as well as cause tissue damage25,73,74; second, TH2 cells that are generated in response to infection with Chlamydia spp. might downregulate the protective TH1-type immune responses, thereby promoting persistent infection49,75,76,77; third, host and Chlamydia-derived antigens (such as HSP60) are recognized by autoreactive T and B cells through MOLECULAR MIMICRY78,79,80; and fourth, C. trachomatis-specific CD4+ and CD8+ T-cell epitopes are often identified in C. trachomatis-associated chronic infections, such as reactive arthritis81,82.
By contrast, the cellular hypothesis (based on the deleterious effects of some cytokines) is supported by the finding that pro-inflammatory cytokines, such as transforming growth factor-β, TNF, IL-1α and IL-6, are secreted by cells infected with Chlamydia spp.23,24 So, persistent infection might induce the secretion of pro-inflammatory cytokines, leading to chronic inflammatory cellular responses and tissue damage83,84.
An alternative proposal that might reconcile the two competing hypotheses stems from the observation that IL-10-deficient mice are more resistant to infection with C. muridarum and have a shorter course of infection than wild-type mice76,77. Regulatory T cells produce IL-10 (Refs 85,86) and might be important in the pathogenesis caused by Chlamydia spp. For example, T cells that are reactive to C. trachomatis HSP60 and produce IL-10 have been found in infertile women87 and therefore might be involved in the suppression of C. trachomatis-specific responses, which could contribute to the ability of C. trachomatis to persist. Although T cells with regulatory properties have been described in the mouse FGT88, the effect of regulatory T cells has not been examined in infections with C. trachomatis, and this warrants further investigation.
Vaccine development
Developing a vaccine against C. trachomatis remains a challenge. In part, this results from our poor understanding of the regulation of the immune response in the FGT (which seems to be highly influenced by sex hormones) (Box 3), the lack of adjuvants that target vaccines to the genital mucosa, our limited knowledge of which C. trachomatis antigens induce protective immune responses and the absence of tools to genetically manipulate Chlamydia spp.89 The observation that the immune response is directly or indirectly involved in the pathogenesis of disease caused by Chlamydia spp. also introduces further complexity to the vaccine-development process90. Nonetheless, the substantial progress that has been made in elucidating the immunobiology of C. muridarum infection is greatly facilitating a renewed effort to design a vaccine against infection with C. trachomatis. Selection of defined antigens for a recombinant subunit vaccine that stimulates CD4+ TH1 cells is central to the current design strategy.
Subunit vaccines. Initial human vaccine trials involved intramuscular administration of whole inactivated C. trachomatis elementary bodies37, which led to the development of partial short-lived protection. However, in some individuals, the vaccine seemed to exacerbate disease during re-infection episodes37,90. As a consequence, the focus of C. trachomatis vaccine research has now turned to the production of subunit vaccines that are based on individual C. trachomatis protein antigens, which are administered with adjuvant or other delivery vehicles. As described earlier, T-cell-mediated immune responses are the main requirement for controlling C. trachomatis infection, and several antigens that trigger T-cell responses have been identified in humans and in mice. C. trachomatis proteins that are recognized by CD4+ or CD8+ T cells in various C. trachomatis-related infections57,82,91,92,93,94,95,96,97 are shown in Table 2.
Selecting antigens. Because immune protection against infection with C. trachomatis is likely to be mediated by immunization with C. trachomatis proteins that are targets of CD4+ and possibly CD8+ T cells, identification of such proteins is particularly important. Considerable progress has been made during the past seven years in the characterization of eight C. trachomatis proteins that are targets for T-cell recognition (Table 2). When the inclusion-membrane-associated protein CrpA (cysteine-rich protein A), which contains C. trachomatis-specific CD8+ T-cell epitopes, is injected into mice, partial protection against challenge with C. trachomatis is observed57. Similarly, Cap1 (class I accessible protein 1) — another C. trachomatis inclusion-membrane-associated protein, which has high homology among the human C. trachomatis serovars — also contains T-cell epitopes, thereby making it a potential vaccine candidate97. However, the most studied and most promising vaccine candidate is C. trachomatis MOMP. MOMP constitutes ∼60% of the total protein mass of the bacterial outer membrane and is 84–97% identical (at the amino-acid level) between the many C. trachomatis serovars70. MOMP has four variable domains, which contain serovar-specific epitopes, and five constant domains, which are highly conserved between the different serovars and which contain several conserved CD4+ and CD8+ T-cell epitopes98. Another vaccine candidate is C. trachomatis outer-membrane protein 2 (OMP2). OMP2 is also an immunodominant antigen that contains CD4+ and CD8+ T-cell epitopes (Table 2). It is more highly conserved in amino-acid sequence among different C. trachomatis serovars than MOMP99; therefore, in a vaccine, it could provide protection against the different C. trachomatis serovars. Recent experiments have shown that inclusion of OMP2 considerably improves the protective potential of MOMP-based vaccines (discussed later). Other potential protective antigens that contain known T-cell epitopes include HSP60, YopD homologue (homologue of Yersinia pseudotuberculosis YopD), enolase and PmpD (polymorphic membrane protein D) (Table 2). However, whether these T-cell antigens provide immune protection remains to be determined.
Other C. trachomatis T-cell antigens for potential incorporation in a vaccine include secreted components of the C. trachomatis TYPE III SECRETION SYSTEM100 — the principal virulence mechanism of the organism. Because proteins secreted by this system enter the cytosol, they are likely to enter the MHC class I antigen processing and presentation pathway and be targets for recognition by CD8+ T cells. Further candidate vaccine antigens might also be revealed by analysis of peptides eluted from MHC class I and class II molecules expressed by DCs pulsed with Chlamydia spp.36,101
For the design of a vaccine against infection with C. trachomatis, it is also important to consider that some C. trachomatis antigens contain epitopes that might be associated with pathogenic responses that occur through molecular mimicry. For example, C. trachomatis-specific T cells that recognize C. trachomatis OMP2 or HSP60 have been found in patients with reactive arthritis (an autoimmune condition in which HLA-B27-restricted responses are thought to have a role) that was triggered by previous infection with C. trachomatis82 (Table 2). In addition, responses to an OMP2-derived peptide were found to be associated with autoimmune heart disease in a mouse model of C. muridarum-induced myocarditis92. However, this 'pathogenic' epitope is found in the leader peptide of the pro-protein92 and is not likely to be presented to the immune system during natural infection, indicating that an OMP2 protein that lacks the signal sequence might be an acceptable vaccine candidate.
Adjuvants and delivery systems. Because sexually transmitted infections with C. trachomatis are restricted to the genital-tract mucosa, to be effective, a vaccine might need to target the genital mucosal inductive sites or the associated secondary lymphoid tissues. In general, the mucosa-associated lymphoid tissue has been regarded as a compartmentalized immune environment containing inductive sites that interact with effector sites in the same compartment (that is, other mucosae)102. So, mice that were pre-infected intranasally with C. muridarum had enhanced TH1-type protective immunity compared with mice that were infected orally or subcutaneously, and these mice were resistant to re-infection of the genital tract103. By contrast, mice that were immunized intramuscularly with MOMP formulated with the adjuvant ISCOMs (immunostimulating complexes) were found to be better protected against C. muridarum infection of the genital tract than mice that were immunized intranasally with MOMP and ISCOMs104. These results indicate that an appropriate combination of antigen and adjuvant can be successful even if the vaccine is delivered to a non-mucosal site.
Adjuvants and multisubunit vaccines. MOMP has been extensively used in C. trachomatis and C. muridarum vaccination studies, together with a diverse range of adjuvants and vaccine delivery systems, and these studies have shown varying levels of protection105,106,107,108,109,110,111,112. Table 3 lists the results of some C. muridarum vaccination studies. For example, immunization with MOMP DNA has been shown to be highly protective in the lung model of C. muridarum infection113 but not in the genital-tract model110, although at present the reasons for this are not understood. Priming the immune response with MOMP DNA followed by boosting with MOMP protein (formulated with ISCOMs) was found to be highly protective in the lung model of C. muridarum infection108. Although DNA vaccines are a useful experimental tool, their application to human vaccines is uncertain: it has been observed that DNA vaccines are better expressed by transcriptionally active cells of young animals; therefore, they might not be as effective in older humans as in young mice114.
The success of a MOMP-based vaccine might depend on several factors, including the presence of the MOMP epitopes in the correct conformation105, the availability of an appropriate vector to deliver the MOMP antigen and the presence of other antigens in addition to MOMP106. This latter possibility is supported by the finding that, although adoptive transfer of DCs pulsed with whole C. muridarum elementary bodies protected mice against infection of the genital tract, adoptive transfer of DCs pulsed with MOMP alone did not29,115. More recently, it was shown that mice immunized with Vibrio cholerae GHOSTS expressing both MOMP and OMP2 were better protected than mice immunized with V. cholerae ghosts expressing MOMP alone106 (Table 3). Mice immunized with both antigens also had a higher frequency of TH1 cells. These results confirm that MOMP alone is probably not sufficient for providing protection, and they support the idea that an effective vaccine is likely to be based on several C. trachomatis antigens106.
Conclusions and future prospects
The protective immune response to infection with Chlamydia spp. is highly dynamic and involves both innate and adaptive immune responses. Infection of mice with C. muridarum has shown that CD4+ T cells, and possibly CD8+ T cells, producing IFN-γ, as well as B cells, are required to clear infection and to prevent re-infection. However, immune responses that are associated with persistent infection with C. trachomatis seem to induce pathology as a result of chronic inflammation and tissue damage. So, a fine balance between protective immunity and immune-associated disease pathogenesis characterizes the host response to infection with C. trachomatis, and this has an impact on the future design of vaccines.
The search for a vaccine against infection with C. trachomatis continues to be a complex task. Nevertheless, progress has been achieved in the past few years and has led to the identification of various protective C. trachomatis antigens as potential vaccine candidates. Although immunization regimens involving priming with DNA vaccines and boosting with protein-based vaccines have been found to be highly protective in mice, their practical application in humans remains unclear. Given that multisubunit protein vaccines seem to be more effective than vaccines based on single antigens, in future, C. trachomatis vaccine candidates are likely to include various antigens.
C. trachomatis vaccine research will continue to focus on the identification of additional C. trachomatis antigens that induce protective T-cell responses and on the mechanisms that promote protective immunity in the FGT, including the role of DCs in antigen uptake and presentation and the role of pro-inflammatory cytokines in influencing the TH1/TH2 response bias. Further data are required to understand the mechanisms that downregulate the immune response in the FGT, including the effects of sex hormones and the menstrual cycle, as well as the possible regulatory effect of particular T-cell populations. Finally, a better definition of human immune-response correlates with C. trachomatis protective immunity and disease pathogenesis needs to remain an important research priority if we are to develop a vaccine against C. trachomatis infection that has protective and not deleterious effects.
References
World Health Organization. Global Prevalence and Incidence of Selected Curable Sexually Transmitted Infections: Overview and Estimates (World Health Organization, Geneva, 2001).
Parish, W. L. et al. Population-based study of chlamydial infection in China: a hidden epidemic. JAMA 289, 1265–1273 (2003).
Fenton, K. A. et al. Sexual behaviour in Britain: reported sexually transmitted infections and prevalent genital Chlamydia trachomatis infection. Lancet 358, 1851–1854 (2001).
Miller, W. C. et al. Prevalence of chlamydial and gonococcal infections among young adults in the United States. JAMA 291, 2229–2236 (2004).
Plummer, F. A. et al. Cofactors in male–female sexual transmission of human immunodeficiency virus type 1. J. Infect. Dis. 163, 233–239 (1991).
Anttila, T. et al. Serotypes of Chlamydia trachomatis and risk for development of cervical squamous cell carcinoma. JAMA 285, 47–51 (2001).
Gotz, H. et al. Is the increase in notifications of Chlamydia trachomatis infections in Sweden the result of changes in prevalence, sampling frequency or diagnostic methods? Scand. J. Infect. Dis. 34, 28–34 (2002).
Su, H. et al. The effect of doxycycline treatment on the development of protective immunity in a murine model of chlamydial genital infection. J. Infect. Dis. 180, 1252–1258 (1999).
Parks, K. S., Dixon, P. B., Richey, C. M. & Hook, E. W. Spontaneous clearance of Chlamydia trachomatis infection in untreated patients. Sex. Transm. Dis. 24, 229–235 (1997).
Golden, M. R., Schillinger, J. A., Markowitz, L. & St Louis, M. E. Duration of untreated genital infections with Chlamydia trachomatis: a review of the literature. Sex. Transm. Dis. 27, 329–337 (2000).
Joyner, J. L., Douglas, J. M., Foster, M. & Judson, F. N. Persistence of Chlamydia trachomatis infection detected by polymerase chain reaction in untreated patients. Sex. Transm. Dis. 29, 196–200 (2002).
Brunham, R. C. in Chlamydia: Intracellular Biology, Pathogenesis, and Immunity (ed. Stephens, R. S.) 211–238 (American Society for Microbiology Press, Washington DC, 1999).
Igietseme, J. U. & Rank, R. G. Susceptibility to reinfection after a primary chlamydial genital infection is associated with a decrease of antigen-specific T cells in the genital tract. Infect. Immun. 59, 1346–1351 (1991).
Read, T. D. et al. Genome sequences of Chlamydia trachomatis MoPn and Chlamydia pneumoniae AR39. Nucleic Acids Res. 28, 1397–1406 (2000).
Morrison, R. P. & Caldwell, H. D. Immunity to murine chlamydial genital infection. Infect. Immun. 70, 2741–2751 (2002).
Caldwell, H. D. et al. Polymorphisms in Chlamydia trachomatis tryptophan synthase genes differentiate between genital and ocular isolates. J. Clin. Invest. 111, 1757–1769 (2003). These authors show that all genital C. trachomatis isolates encode a functional tryptophan synthase, whereas all ocular isolates have inactivating mutations in the gene that encodes tryptophan synthase. In response to IFN-γ-mediated depletion of local tryptophan, genital C. trachomatis strains use local indole for tryptophan biosynthesis, allowing these strains to escape the inhibitory effects of IFN-γ.
Igietseme, J. U., Eko, F. O. & Black, C. M. Contemporary approaches to designing and evaluating vaccines against Chlamydia. Expert Rev. Vaccines 2, 129–146 (2003).
Schachter, J. in Chlamydia: Intracellular Biology, Pathogenesis, and Immunity (ed. Stephens, R. S.) 139–169 (American Society for Microbiology Press, Washington DC, 1999).
Peipert, J. F. Clinical practice. Genital chlamydial infections. N. Engl. J. Med. 349, 2424–2430 (2003).
Brunham, R. C. et al. Mucopurulent cervicitis — the ignored counterpart in women of urethritis in men. N. Engl. J. Med. 311, 1–6 (1984).
Cohen, C. R. & Brunham, R. C. Pathogenesis of Chlamydia induced pelvic inflammatory disease. Sex. Transm. Infect. 75, 21–24 (1999).
Brunham, R. C. et al. Etiology and outcome of acute pelvic inflammatory disease. J. Infect. Dis. 158, 510–517 (1988).
Rasmussen, S. J. et al. 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. 99, 77–87 (1997). These authors show that chlamydial infection of cervical epithelium upregulates the expression of several pro-inflammatory cytokines, including CXCL1, CXCL8, GM-CSF, IL-1α and IL-6. Induction of these mediators was shown to persist throughout the chlamydial life cycle, indicating that they might be involved in disease exacerbation.
Johnson, R. M. Murine oviduct epithelial cell cytokine responses to Chlamydia muridarum infection include interleukin-12-p70 secretion. Infect. Immun. 72, 3951–3960 (2004).
Maxion, H. K. & Kelly, K. A. Chemokine expression patterns differ within anatomically distinct regions of the genital tract during Chlamydia trachomatis infection. Infect. Immun. 70, 1538–1546 (2002). This study shows that levels of T H 1-cell-associated chemokines (such as CXCL9, CXCL10 and CCL5) are considerably higher in the upper FGT than in the lower FGT in mice infected with C. trachomatis , indicating that the upper and lower FGT respond differently to infection with C. trachomatis.
Devitt, A., Lund, P. A., Morris, A. G. & Pearce, J. H. Induction of α/β interferon and dependent nitric oxide synthesis during Chlamydia trachomatis infection of McCoy cells in the absence of exogenous cytokine. Infect. Immun. 64, 3951–3956 (1996).
Darville, T. et al. Toll-like receptor-2, but not Toll-like receptor-4, is essential for development of oviduct pathology in chlamydial genital tract infection. J. Immunol. 171, 6187–6197 (2003). This study shows that, in response to in vitro infection with Chlamydia spp., TLR2-deficient macrophages or fibroblasts produce less pro-inflammatory cytokines than either TLR4-deficient cells or wild-type cells. In vivo infection studies show that TLR2-deficient mice have less chronic oviduct pathology than either TLR4-deficient mice or wild-type mice, indicating that TLR2 is involved in promoting tissue pathology.
Iwasaki, A. & Medzhitov, R. Toll-like receptor control of the adaptive immune responses. Nature Immunol. 5, 987–995 (2004).
Su, H. et al. Vaccination against chlamydial genital tract infection after immunization with dendritic cells pulsed ex vivo with nonviable chlamydiae. J. Exp. Med. 188, 809–818 (1998). This study shows that adoptive transfer of DCs pulsed ex vivo with heat-killed C. trachomatis induces protective immunity and high levels of protection against infection with C. trachomatis . This indicates that targeting DCs might be required for effective immune protection.
Lu, H. & Zhong, G. Interleukin-12 production is required for chlamydial antigen-pulsed dendritic cells to induce protection against live Chlamydia trachomatis infection. Infect. Immun. 67, 1763–1769 (1999).
Shaw, J. H., Grund, V. R., Durling, L. & Caldwell, H. D. Expression of genes encoding TH1 cell-activating cytokines and lymphoid homing chemokines by Chlamydia-pulsed dendritic cells correlates with protective immunizing efficacy. Infect. Immun. 69, 4667–4672 (2001).
Prebeck, S. et al. Predominant role of Toll-like receptor 2 versus 4 in Chlamydia pneumoniae-induced activation of dendritic cells. J. Immunol. 167, 3316–3323 (2001).
Parr, M. B., Kepple, L. & Parr, E. L. Langerhans cells phagocytose vaginal epithelial cells undergoing apoptosis during the murine estrous cycle. Biol. Reprod. 45, 252–260 (1991).
Zhang, D., Yang, X., Lu, H., Zhong, G. & Brunham, R. C. 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. 67, 1606–1613 (1999).
Neutra, M. R., Pringault, E. & Kraehenbuhl, J. P. Antigen sampling across epithelial barriers and induction of mucosal immune responses. Annu. Rev. Immunol. 14, 275–300 (1996).
Rey-Ladino, J., Koochesfahani, K. M., Zaharik, M. L., Shen, C. & Brunham, R. C. Live and inactivated Chlamydia trachomatis mouse pneumonitis (MoPn) induce the maturation of dendritic cells that are phenotypically and immunologically distinct. Infect. Immun. (in the press).
Grayston, J. T. & Wang, S. P. The potential for vaccine against infection of the genital tract with Chlamydia trachomatis. Sex. Transm. Dis. 5, 73–77 (1978).
Steinman, R. M., Turley, S., Mellman, I. & Inaba, K. The induction of tolerance by dendritic cells that have captured apoptotic cells. J. Exp. Med. 191, 411–416 (2000).
Zuercher, A. W., Coffin, S. E., Thurnheer, M. C., Fundova, P. & Cebra, J. J. Nasal-associated lymphoid tissue is a mucosal inductive site for virus-specific humoral and cellular immune responses. J. Immunol. 168, 1796–1803 (2002).
Morrison, S. G. & Morrison, R. P. In situ analysis of the evolution of the primary immune response in murine Chlamydia trachomatis genital tract infection. Infect. Immun. 68, 2870–2879 (2000).
Kiviat, N. B. et al. Endometrial histopathology in patients with culture-proved upper genital tract infection and laparoscopically diagnosed acute salpingitis. Am. J. Surg. Pathol. 14, 167–175 (1990).
Patton, D. L. & Taylor, H. R. The histopathology of experimental trachoma: ultrastructural changes in the conjunctival epithelium. J. Infect. Dis. 153, 870–878 (1986).
Kelly, K. A. et al. Chlamydia trachomatis infection induces mucosal addressin cell adhesion molecule-1 and vascular cell adhesion molecule-1, providing an immunologic link between the fallopian tube and other mucosal tissues. J. Infect. Dis. 184, 885–891 (2001). This article shows that expression of the adhesion molecules VCAM1 and MADCAM1, which are required for lymphocyte recruitment to inflammatory sites, is induced in fallopian tubes stimulated with C. trachomatis . Because similar events occur in other mucosae during inflammation, this indicates the existence of common lymphocyte-recruitment mechanisms at mucosal sites.
Mitchell, E. A. et al. Homing of mononuclear cells from iliac lymph nodes to the genital and rectal mucosa in non-human primates. Eur. J. Immunol. 28, 3066–3074 (1998).
King, N. J., Parr, E. L. & Parr, M. B. Migration of lymphoid cells from vaginal epithelium to iliac lymph nodes in relation to vaginal infection by herpes simplex virus type 2. J. Immunol. 160, 1173–1180 (1998).
Rank, R. G., Soderberg, L. S. & Barron, A. L. Chronic chlamydial genital infection in congenitally athymic nude mice. Infect. Immun. 48, 847–849 (1985).
Ramsey, K. H. & Rank, R. G. Resolution of chlamydial genital infection with antigen-specific T-lymphocyte lines. Infect. Immun. 59, 925–931 (1991).
Su, H. & Caldwell, H. D. CD4+ T cells play a significant role in adoptive immunity to Chlamydia trachomatis infection of the mouse genital tract. Infect. Immun. 63, 3302–3308 (1995).
Wang, S., Fan, Y., Brunham, R. C. & Yang, X. IFN-γ knockout mice show TH2-associated delayed-type hypersensitivity and the inflammatory cells fail to localize and control chlamydial infection. Eur. J. Immunol. 29, 3782–3792 (1999).
Morrison, R. P., Feilzer, K. & Tumas, D. B. Gene knockout mice establish a primary protective role for major histocompatibility complex class II-restricted responses in Chlamydia trachomatis genital tract infection. Infect. Immun. 63, 4661–4668 (1995).
Morrison, S. G., Su, H., Caldwell, H. D. & Morrison, R. P. Immunity to murine Chlamydia trachomatis genital tract reinfection involves B cells and CD4+ T cells but not CD8+ T cells. Infect. Immun. 68, 6979–6987 (2000). These authors show that both B cells and CD4+ T cells are required to control chlamydial infection. Depletion of CD4+ T cells, but not CD8+ T cells, from immune B-cell-deficient mice altered the course of secondary infection such that these mice did not resolve secondary infection.
Perry, L. L., Feilzer, K. & Caldwell, H. D. Immunity to Chlamydia trachomatis is mediated by T helper 1 cells through IFN-γ-dependent and -independent pathways. J. Immunol. 158, 3344–3352 (1997).
Johansson, M., Schon, K., Ward, M. & Lycke, N. Genital tract infection with Chlamydia trachomatis fails to induce protective immunity in γ-interferon receptor-deficient mice despite a strong local immunoglobulin A response. Infect. Immun. 65, 1032–1044 (1997).
Hawkins, R. A., Rank, R. G. & Kelly, K. A. A Chlamydia trachomatis-specific TH2 clone does not provide protection against a genital infection and displays reduced trafficking to the infected genital mucosa. Infect. Immun. 70, 5132–5139 (2002).
Perry, L. L., Feilzer, K., Hughes, S. & Caldwell, H. D. Clearance of Chlamydia trachomatis from the murine genital mucosa does not require perforin-mediated cytolysis or Fas-mediated apoptosis. Infect. Immun. 67, 1379–1385 (1999).
Beatty, P. R. & Stephens, R. S. CD8+ T lymphocyte-mediated lysis of Chlamydia-infected L cells using an endogenous antigen pathway. J. Immunol. 153, 4588–4595 (1994).
Starnbach, M. N. et al. An inclusion membrane protein from Chlamydia trachomatis enters the MHC class I pathway and stimulates a CD8+ T cell response. J. Immunol. 171, 4742–4749 (2003). In this study, C. trachomatis -specific T cells were used to identify a chlamydial protein known as CrpA. This protein is recognized by CD8+ T cells, and mice immunized with CrpA were partially protected against infection with C. trachomatis.
Beatty, W. L., Belanger, T. A., Desai, A. A., Morrison, R. P. & Byrne, G. I. Tryptophan depletion as a mechanism of γ-interferon-mediated chlamydial persistence. Infect. Immun. 62, 3705–3711 (1994).
Fehlner-Gardiner, C. et al. Molecular basis defining human Chlamydia trachomatis tissue tropism. A possible role for tryptophan synthase. J. Biol. Chem. 277, 26893–26903 (2002).
Ramsey, K. H. et al. Role for inducible nitric oxide synthase in protection from chronic Chlamydia trachomatis urogenital disease in mice and its regulation by oxygen free radicals. Infect. Immun. 69, 7374–7379 (2001).
Brunham, R. C., Kuo, C. C., Cles, L. & Holmes, K. K. Correlation of host immune response with quantitative recovery of Chlamydia trachomatis from the human endocervix. Infect. Immun. 39, 1491–1494 (1983). This study shows that the amount of secretory IgA specific for C. trachomatis in the cervical secretion inversely correlates with the amount of C. trachomatis that is recovered from the cervix, indicating that C. trachomatis -specific antibodies regulate chlamydial shedding in the human FGT.
Byrne, G. I. et al. Workshop on in vitro neutralization of Chlamydia trachomatis: summary of proceedings. J. Infect. Dis. 168, 415–420 (1993).
Punnonen, R., Terho, P., Nikkanen, V. & Meurman, O. Chlamydial serology in infertile women by immunofluorescence. Fertil. Steril. 31, 656–659 (1979).
Ramsey, K. H., Soderberg, L. S. & Rank, R. G. Resolution of chlamydial genital infection in B-cell-deficient mice and immunity to reinfection. Infect. Immun. 56, 1320–1325 (1988).
Morrison, S. G. & Morrison, R. P. Resolution of secondary Chlamydia trachomatis genital tract infection in immune mice with depletion of both CD4+ and CD8+ T cells. Infect. Immun. 69, 2643–2649 (2001).
Moore, T. et al. Fc receptor-mediated antibody regulation of T cell immunity against intracellular pathogens. J. Infect. Dis. 188, 617–624 (2003).
Moore, T. et al. Fc receptor regulation of protective immunity against Chlamydia trachomatis. Immunology 105, 213–221 (2002).
Igietseme, J. U., Eko, F. O., He, Q. & Black, C. M. Antibody regulation of T cell immunity: implications for vaccine strategies against intracellular pathogens. Expert Rev. Vaccines 3, 23–34 (2004).
Rank, R. G. in Chlamydia: Intracellular Biology, Pathogenesis, and Immunity (ed. Stephens, R. S.) 239–295 (American Society for Microbiology Press, Washington DC, 1999).
Brunham, R. C. & Peeling, R. W. Chlamydia trachomatis antigens: role in immunity and pathogenesis. Infect. Agents Dis. 3, 218–233 (1994).
Kinnunen, A. et al. Chlamydia trachomatis reactive T lymphocytes from upper genital tract tissue specimens. Hum. Reprod. 15, 1484–1489 (2000).
Stephens, R. S. The cellular paradigm of chlamydial pathogenesis. Trends Microbiol. 11, 44–51 (2003).
Rank, R. G., Bowlin, A. K. & Kelly, K. A. Characterization of lymphocyte response in the female genital tract during ascending chlamydial genital infection in the guinea pig model. Infect. Immun. 68, 5293–5298 (2000). These authors show that, compared with primary infection with Chlamydophila psittaci , after re-infection, the number of CD4+ and CD8+ T cells, as well as B cells, is markedly increased in the fallopian tubes of guinea pigs. This indicates that a cell-mediated immune response associated with pathology occurs during re-infection.
Van Voorhis, W. C., Barrett, L. K., Sweeney, Y. T., Kuo, C. C. & Patton, D. L. Repeated Chlamydia trachomatis infection of Macaca nemestrina fallopian tubes produces a TH1-like cytokine response associated with fibrosis and scarring. Infect. Immun. 65, 2175–2182 (1997). These authors found that fallopian-tube tissues that are repeatedly infected with C. trachomatis are infiltrated with CD8+ T cells. Furthermore, deposition of fibrotic tissue occurred, as well as production of IFN-γ, IL-2, IL-6 and IL-10 (but not IL-4), indicating that all of these events might contribute to scarring of the upper genital tract.
Holland, M. J. et al. T helper type-1 (TH1)/TH2 profiles of peripheral blood mononuclear cells (PBMC); responses to antigens of Chlamydia trachomatis in subjects with severe trachomatous scarring. Clin. Exp. Immunol. 105, 429–435 (1996).
Yang, X., Gartner, J., Zhu, L., Wang, S. & Brunham, R. C. IL-10 gene knockout mice show enhanced TH1-like protective immunity and absent granuloma formation following Chlamydia trachomatis lung infection. J. Immunol. 162, 1010–1017 (1999).
Igietseme, J. U. et al. Suppression of endogenous IL-10 gene expression in dendritic cells enhances antigen presentation for specific TH1 induction: potential for cellular vaccine development. J. Immunol. 164, 4212–4219 (2000).
Yi, Y., Yang, X. & Brunham, R. C. Autoimmunity to heat shock protein 60 and antigen-specific production of interleukin-10. Infect. Immun. 65, 1669–1674 (1997).
Peeling, R. W. et al. Antibody to chlamydial HSP60 predicts an increased risk for chlamydial pelvic inflammatory disease. J. Infect. Dis. 175, 1153–1158 (1997).
Lichtenwalner, A. B., Patton, D. L., Van Voorhis, W. C., Sweeney, Y. T. & 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. 72, 1159–1161 (2004).
Hassell, A. B., Reynolds, D. J., Deacon, M., Gaston, J. S. & Pearce, J. H. Identification of T-cell stimulatory antigens of Chlamydia trachomatis using synovial fluid-derived T-cell clones. Immunology 79, 513–519 (1993).
Goodall, J. C., Yeo, G., Huang, M., Raggiaschi, R. & Gaston, J. S. Identification of Chlamydia trachomatis antigens recognized by human CD4+ T lymphocytes by screening an expression library. Eur. J. Immunol. 31, 1513–1522 (2001).
Cappuccio, A. L., Patton, D. L., Kuo, C. C. & Campbell, L. A. Detection of Chlamydia trachomatis deoxyribonucleic acid in monkey models (Macaca nemestrina) of salpingitis by in situ hybridization: implications for pathogenesis. Am. J. Obstet. Gynecol. 171, 102–110 (1994).
Hogan, R. J., Mathews, S. A., Mukhopadhyay, S., Summersgill, J. T. & Timms, P. Chlamydial persistence: beyond the biphasic paradigm. Infect. Immun. 72, 1843–1855 (2004).
Sakaguchi, S. Regulatory T cells: mediating compromises between host and parasite. Nature Immunol. 4, 10–11 (2003).
O'Garra, A., Vieira, P. L., Vieira, P. & Goldfeld, A. E. IL-10-producing and naturally occurring CD4+ TRegs: limiting collateral damage. J. Clin. Invest. 114, 1372–1378 (2004).
Kinnunen, A. et al. Chlamydia trachomatis heat shock protein-60 induced interferon-γ and interleukin-10 production in infertile women. Clin. Exp. Immunol. 131, 299–303 (2003).
Johansson, M. & Lycke, N. A unique population of extrathymically derived αβ TCR+CD4−CD8− T cells with regulatory functions dominates the mouse female genital tract. J. Immunol. 170, 1659–1666 (2003).
Igietseme, J. U., Black, C. M. & Caldwell, H. D. Chlamydia vaccines: strategies and status. BioDrugs 16, 19–35 (2002).
Grayston, J. T., Wang, S. P., Yeh, L. J. & Kuo, C. C. Importance of reinfection in the pathogenesis of trachoma. Rev. Infect. Dis. 7, 717–725 (1985).
Gervassi, A. L. et al. Human CD8+ T cells recognize the 60-kDa cysteine-rich outer membrane protein from Chlamydia trachomatis. J. Immunol. 173, 6905–6913 (2004).
Bachmaier, K. et al. Chlamydia infections and heart disease linked through antigenic mimicry. Science 283, 1335–1339 (1999).
Holland, M. J. et al. Synthetic peptides based on Chlamydia trachomatis antigens identify cytotoxic T lymphocyte responses in subjects from a trachoma-endemic population. Clin. Exp. Immunol. 107, 44–49 (1997).
Kim, S. K., Devine, L., Angevine, M., DeMars, R. & Kavathas, P. B. Direct detection and magnetic isolation of Chlamydia trachomatis major outer membrane protein-specific CD8+ CTLs with HLA class I tetramers. J. Immunol. 165, 7285–7292 (2000).
Ortiz, L., Angevine, M., Kim, S. K., Watkins, D. & DeMars, R. T-cell epitopes in variable segments of Chlamydia trachomatis major outer membrane protein elicit serovar-specific immune responses in infected humans. Infect. Immun. 68, 1719–1723 (2000).
Deane, K. H., Jecock, R. M., Pearce, J. H. & Gaston, J. S. Identification and characterization of a DR4-restricted T cell epitope within Chlamydia heat shock protein 60. Clin. Exp. Immunol. 109, 439–445 (1997).
Fling, S. P. et al. CD8+ T cells recognize an inclusion membrane-associated protein from the vacuolar pathogen Chlamydia trachomatis. Proc. Natl Acad. Sci. USA 98, 1160–1165 (2001).
Kim, S. K. & DeMars, R. Epitope clusters in the major outer membrane protein of Chlamydia trachomatis. Curr. Opin. Immunol. 13, 429–436 (2001).
Portig, I., Goodall, J. C., Bailey, R. L. & Gaston, J. S. Characterization of the humoral immune response to Chlamydia outer membrane protein 2 in chlamydial infection. Clin. Diagn. Lab. Immunol. 10, 103–107 (2003).
Clifton, D. R. et al. A chlamydial type III translocated protein is tyrosine-phosphorylated at the site of entry and associated with recruitment of actin. Proc. Natl Acad. Sci. USA 101, 10166–10171 (2004).
Dongre, A. R. et al. In vivo MHC class II presentation of cytosolic proteins revealed by rapid automated tandem mass spectrometry and functional analyses. Eur. J. Immunol. 31, 1485–1494 (2001).
Moldoveanu, Z. et al. Compartmentalization within the common mucosal immune system. Adv. Exp. Med. Biol. 371A, 97–101 (1995).
Igietseme, J. U. et al. Route of infection that induces a high intensity of γ interferon-secreting T cells in the genital tract produces optimal protection against Chlamydia trachomatis infection in mice. Infect. Immun. 66, 4030–4035 (1998).
Igietseme, J. U. & 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. 68, 6798–6806 (2000).
Pal, S., Theodor, I., Peterson, E. M. & de la Maza, L. M. Immunization with the Chlamydia trachomatis mouse pneumonitis major outer membrane protein can elicit a protective immune response against a genital challenge. Infect. Immun. 69, 6240–6247 (2001).
Eko, F. O. et al. A novel recombinant multisubunit vaccine against Chlamydia. J. Immunol. 173, 3375–3382 (2004). In this study, recombinant V. cholerae ghosts that express both C. trachomatis OMP2 and MOMP were developed. Immunization of mice with this preparation resulted in a T H 1-type immune response and high levels of protection against infection with C. trachomatis.
Eko, F. O. et al. Recombinant Vibrio cholerae ghosts as a delivery vehicle for vaccinating against Chlamydia trachomatis. Vaccine 21, 1694–1703 (2003).
Dong-Ji, Z. et al. Priming with Chlamydia trachomatis major outer membrane protein (MOMP) DNA followed by MOMP ISCOM boosting enhances protection and is associated with increased immunoglobulin A and TH1 cellular immune responses. Infect. Immun. 68, 3074–3078 (2000).
Berry, L. J. et al. Transcutaneous immunization with combined cholera toxin and CpG adjuvant protects against Chlamydia muridarum genital tract infection. Infect. Immun. 72, 1019–1028 (2004).
Pal, S. et al. Vaccination of mice with DNA plasmids coding for the Chlamydia trachomatis major outer membrane protein elicits an immune response but fails to protect against a genital challenge. Vaccine 17, 459–465 (1999).
Pal, S., Luke, C. J., Barbour, A. G., Peterson, E. M. & de la Maza, L. M. Immunization with the Chlamydia trachomatis major outer membrane protein, using the outer surface protein A of Borrelia burgdorferi as an adjuvant, can induce protection against a chlamydial genital challenge. Vaccine 21, 1455–1465 (2003).
Zhang, D. J., Yang, X., Shen, C. & Brunham, R. C. Characterization of immune responses following intramuscular DNA immunization with the MOMP gene of Chlamydia trachomatis mouse pneumonitis strain. Immunology 96, 314–321 (1999).
Zhang, D. et al. DNA vaccination with the major outer-membrane protein gene induces acquired immunity to Chlamydia trachomatis (mouse pneumonitis) infection. J. Infect. Dis. 176, 1035–1040 (1997).
Barry, M. A. & Johnston, S. A. Biological features of genetic immunization. Vaccine 15, 788–791 (1997).
Shaw, J., Grund, V., Durling, L., Crane, D. & Caldwell, H. D. Dendritic cells pulsed with a recombinant chlamydial major outer membrane protein antigen elicit a CD4+ type 2 rather than type 1 immune response that is not protective. Infect. Immun. 70, 1097–1105 (2002).
Brunham, R. C., Plummer, F. A. & Stephens, R. S. Bacterial antigenic variation, host immune response, and pathogen–host coevolution. Infect. Immun. 61, 2273–2276 (1993).
Fields, K. A. & Hackstadt, T. The chlamydial inclusion: escape from the endocytic pathway. Annu. Rev. Cell Dev. Biol. 18, 221–245 (2002).
Fan, T. et al. Inhibition of apoptosis in Chlamydia-infected cells: blockade of mitochondrial cytochrome c release and caspase activation. J. Exp. Med. 187, 487–496 (1998).
Hogbom, M. et al. The radical site in chlamydial ribonucleotide reductase defines a new R2 subclass. Science 305, 245–248 (2004).
Ingalls, R. R. et al. The inflammatory cytokine response to Chlamydia trachomatis infection is endotoxin mediated. Infect. Immun. 63, 3125–3130 (1995).
Jendro, M. C. et al. Chlamydia trachomatis-infected macrophages induce apoptosis of activated T cells by secretion of tumor necrosis factor-α in vitro. Med. Microbiol. Immunol. (Berl.) 193, 45–52 (2004).
Zhong, G., Liu, L., Fan, T., Fan, P. & Ji, H. Degradation of transcription factor RFX5 during the inhibition of both constitutive and interferon γ-inducible major histocompatibility complex class I expression in Chlamydia-infected cells. J. Exp. Med. 191, 1525–1534 (2000).
Beatty, W. L., Morrison, R. P. & Byrne, G. I. Persistent chlamydiae: from cell culture to a paradigm for chlamydial pathogenesis. Microbiol. Rev. 58, 686–699 (1994).
Belland, R. J. et al. Transcriptome analysis of chlamydial growth during IFN-γ-mediated persistence and reactivation. Proc. Natl Acad. Sci. USA 100, 15971–15976 (2003).
Morrison, R. P. New insights into a persistent problem — chlamydial infections. J. Clin. Invest. 111, 1647–1649 (2003).
Wood, H. et al. Regulation of tryptophan synthase gene expression in Chlamydia trachomatis. Mol. Microbiol. 49, 1347–1359 (2003).
Johansson, M. & Lycke, N. Y. Immunology of the human genital tract. Curr. Opin. Infect. Dis. 16, 43–49 (2003).
Russell, M. W. Immunization for protection of the reproductive tract: a review. Am. J. Reprod. Immunol. 47, 265–268 (2002).
Beagley, K. W. & Gockel, C. M. Regulation of innate and adaptive immunity by the female sex hormones oestradiol and progesterone. FEMS Immunol. Med. Microbiol. 38, 13–22 (2003).
Tlaskalova-Hogenova, H. et al. Commensal bacteria (normal microflora), mucosal immunity and chronic inflammatory and autoimmune diseases. Immunol. Lett. 93, 97–108 (2004).
Mestecky, J. & Fultz, P. N. Mucosal immune system of the human genital tract. J. Infect. Dis. 179 (Suppl. 3), S470–S474 (1999).
Yeaman, G. R. et al. Unique CD8+ T cell-rich lymphoid aggregates in human uterine endometrium. J. Leukoc. Biol. 61, 427–435 (1997).
Walmer, D. K., Wrona, M. A., Hughes, C. L. & Nelson, K. G. Lactoferrin expression in the mouse reproductive tract during the natural estrous cycle: correlation with circulating estradiol and progesterone. Endocrinology 131, 1458–1466 (1992).
Henderson, T. A., Saunders, P. T., Moffett-King, A., Groome, N. P. & Critchley, H. O. Steroid receptor expression in uterine natural killer cells. J. Clin. Endocrinol. Metab. 88, 440–449 (2003).
White, H. D. et al. CD3+ CD8+ CTL activity within the human female reproductive tract: influence of stage of the menstrual cycle and menopause. J. Immunol. 158, 3017–3027 (1997).
Piccinni, M. P. et al. Progesterone favors the development of human T helper cells producing TH2-type cytokines and promotes both IL-4 production and membrane CD30 expression in established TH1 cell clones. J. Immunol. 155, 128–133 (1995).
Rank, R. G., Sanders, M. M. & Kidd, A. T. Influence of the estrous cycle on the development of upper genital tract pathology as a result of chlamydial infection in the guinea pig model of pelvic inflammatory disease. Am. J. Pathol. 142, 1291–1296 (1993).
Kaushic, C., Murdin, A. D., Underdown, B. J. & Wira, C. R. Chlamydia trachomatis infection in the female reproductive tract of the rat: influence of progesterone on infectivity and immune response. Infect. Immun. 66, 893–898 (1998).
Kozlowski, P. A. et al. Differential induction of mucosal and systemic antibody responses in women after nasal, rectal, or vaginal immunization: influence of the menstrual cycle. J. Immunol. 169, 566–574 (2002).
Hackstadt, T., Fischer, E. R., Scidmore, M. A., Rockey, D. D. & Heinzen, R. A. Origins and functions of the chlamydial inclusion. Trends Microbiol. 5, 288–293 (1997).
Acknowledgements
This work was carried out in the laboratory of R.C.B. and is supported by grants from the Canadian Institutes of Health Research.
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R. C. Brunham's research group receives financial support from Sanofi-Avent is for evaluation of Chlamydia vaccine antigens; however, this work is not reflected in the contents of the review article.
Glossary
- PELVIC INFLAMMATORY DISEASE
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(PID). Infection of the upper compartment of the female genital tract, which includes the uterus, fallopian tubes, ovaries and related structures.
- ECTOPIC PREGNANCY
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Pregnancy in which the fertilized egg implants and the fetus begins to develop in tissues other than the normal lining of the endometrium.
- SALPINGITIS
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Inflammatory disease involving the fallopian tubes, which often occurs as a result of infection.
- MUCOPURULENT CERVICITIS
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Inflammatory disease of the endocervix, which is most often a result of sexually transmitted infection, such as infection with Chlamydia trachomatis.
- NON-GONOCOCCAL URETHRITIS
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Inflammatory discharge from the male urethra, which is most often a result of sexually transmitted infection, such as infection with Chlamydia trachomatis.
- HYPERTROPHIC CERVICAL ECTOPY
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Distinctive oedema of the columnar epithelium in the female endocervix. This is usually a feature of mucopurulent cervicitis and is often a result of sexually transmitted infection, such as infection with Chlamydia trachomatis.
- PEYER'S PATCHES
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Specialized lymphoid follicles localized in the submucosa of the small intestine and appendix.
- COMMON MUCOSAL IMMUNE SYSTEM
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It has been proposed that specialized dynamics of immunity occur in the mucosal compartment. This model considers, for example, that lymphocytes that originate in mucosal inductive sites will home to mucosal effector sites.
- LAMINA PROPRIA
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Connective tissue that underlies the epithelium of the mucosa and contains various myeloid and lymphoid cells, including macrophages, dendritic cells, T cells and B cells.
- MOLECULAR MIMICRY
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When a microbial protein has structural and sequence similarity to a host protein, the immune response can trigger a crossreactive autoimmune attack.
- TYPE III SECRETION SYSTEM
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A specialized molecular machine present in some bacteria that allows translocation of bacterial proteins into host cells.
- GHOSTS
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Lysis of the cytoplasmic membrane of Gram-negative bacteria while maintaining the outer membrane intact generates bacterial ghosts that are useful for antigen delivery.
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Brunham, R., Rey-Ladino, J. Immunology of Chlamydia infection: implications for a Chlamydia trachomatis vaccine. Nat Rev Immunol 5, 149–161 (2005). https://doi.org/10.1038/nri1551
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DOI: https://doi.org/10.1038/nri1551
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