Arch Gynecol Obstet DOI 10.1007/s00404-013-3122-3


Chlamydia trachomatis infection: implications for HPV status and cervical cancer Jani Silva • Fa´tima Cerqueira • Rui Medeiros

Received: 2 July 2013 / Accepted: 4 December 2013 Ó Springer-Verlag Berlin Heidelberg 2013

Abstract Genital Chlamydia trachomatis (CT) infections have been identified as a major health problem concern. CT is associated with adverse effect on women reproduction and also associated with cervical hypertrophy and induction of squamous metaplasia, providing a possible relationship with human papillomavirus (HPV) infection. Infection by high-risk HPV types is crucial to the pathogenesis of invasive cervical cancer (ICC), but other covariants/cofactors must be present for the development of malignancy. CT biological effect may damage the mucosal barrier, improving HPV infection, or may interfere in J. Silva  R. Medeiros (&) Grupo Oncologia Molecular-CI, Laborato´rios Piso 4, Instituto Portugueˆs de Oncologia do Porto FG, EPE, Rua Dr. Anto´nio Bernardino Almeida, 4200-072 Porto, Portugal e-mail: [email protected]

immune response and viral clearance supporting the persistence of HPV infection. Moreover, CT-related chronic cervical inflammation, decrease of lower genital tract antigen-presenting cells, inhibition of cell-mediated immunity, and anti-apoptotic capacity may influence the natural history of HPV infection, namely persistence progression or resolution. Although several epidemiological studies have stated a positive association involving CT and HPV-related cervical neoplastic lesions and/or cervical cancer (CC), the specific role of this bacterium in the pathogenesis of cervical neoplasia has not been completely clarified. The present review summarizes several studies on CT role in cervical cancer and suggests future research directions on HPV and CT interaction. Keywords Chlamydia trachomatis  Human papillomavirus  Infection  Cervical cancer

J. Silva Faculty of Medicine, University of Porto, Porto, Portugal J. Silva  F. Cerqueira  R. Medeiros CEBIMED, Faculty of Health Sciences, Fernando Pessoa University, Porto, Portugal J. Silva  R. Medeiros LPCC, Research Department, Portuguese League Against Cancer (LPCC-NRN), Lisbon, Portugal F. Cerqueira CEQUIMED, Faculty of Pharmacy, University of Porto, Porto, Portugal R. Medeiros Molecular Biology Laboratory-Virology Service, Portuguese Institute of Oncology of Porto (IPO Porto), Porto, Portugal R. Medeiros ICBAS, Abel Salazar Institute for the Biomedical Sciences, University of Porto, Porto, Portugal

Introduction Chlamydia trachomatis (CT) is an obligate intracellular pathogen that infects human epithelial cells of the genital tract, as well as ocular tissue. Worldwide, CT is the most prevalent sexually transmitted infection (STI) and has been identified as a major public health problem. The World Health Organization (WHO) estimates that almost 100 million chlamydial cases occur each year [1]. In 2009, CT infection in Europe was reported more often in women than men, with an overall rate of 217/100,000 and 152/100,000, respectively [2]. Despite its mostly asymptomatic infection, CT-related genitourinary infections are a major cause of morbidity in the sexually active women. Furthermore, CT causes gynaecological sequelae, including pelvic inflammatory disease, ectopic pregnancy and tubal factor infertility [3].


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Worldwide, cervical cancer (CC) is the third most common cancer, and the seventh overall, with an estimated 529,000 new cases in 2008 [4]. Persistent infection of highrisk human papillomavirus (HPV) types is on the basis of CC aetiology [5]. Additionally, behavioural factors, host genetic background, individual variation in immune response, or infections with CT [6], Neisseria gonorrhoea [7], bacterial vaginosis or herpes simplex virus type 2 [8, 9], have been associated with cervical inflammation and increased risk of CC. CT has also been studied as a potential co-factor of cervical intraepithelial neoplasia (CIN) and CC [5, 6, 10]. CT targets human endocervical epithelial cells, being women with cervical ectopy more susceptible to infection. Genital tract infection with CT is often chronic, being also related with few symptoms and limited inflammatory signals, resulting in slight or even no symptoms in *70–80 % of women [11, 12]. Persistent chlamydial infection may be related to cervical hypertrophy [13, 14] and induction of squamous metaplasia [3], providing a possible CT/HPV synergic effect in the CC aetiology. Some data suggest that CT has a carcinogenic effect mediated by a decrease of HPV clearance [10, 15]. This review is a summary of several studies outlining the role of CT infection as HPV cofactor in CC aetiology. A search of the literature from 1990 through March 2013 was conducted with selection criteria to identify relevant data in Medline, Web of Science and Embase. The term ‘‘Chlamydia trachomatis’’ was combined with ‘‘co-infection’’, ‘‘human papillomavirus’’, ‘‘low-grade squamous intraepithelial lesion’’, ‘‘high-grade squamous intraepithelial lesion’’, ‘‘cervical intraepithelial neoplasia’’ or ‘‘cervical cancer’’. Additional articles were identified by crosslisting bibliographies of reviewed articles. The selected literature was examined for content, and 39 articles deemed to be most relevant to the key questions selected for this review. Only English language manuscripts were reviewed. The information on study type, population, results, and strengths is discussed narratively in the text.

CT, HPV and CC Chronic inflammation has been related to several epithelial cancers, such as oesophagus, stomach, pancreas, liver, biliary tract, colon, bladder, vulva and cervix [16, 17]. Only a small proportion of women infected with HPV infection progress to ICC. HPV infection is a prerequisite for cervical carcinogenesis, but alone is unlikely to be sufficient, and other risk factors should be considered. Exogenous cofactors (dietary, hormonal contraceptives, smoking habits, parity, multiple sexual partners, and coinfection with other sexually transmitted agents), viral cofactors (infection with high-risk HPV types, coinfection


multiple HPV types, viral load, and viral integration) and host cofactors (endogenous hormones, genetic background, and immune response) could exert its biologic effect in the persistence of HPV infection and progression to CC [18– 24]. Our knowledge of the role of STIs in the natural history of HPV, as well as its action in the development of ICC and its associated precursor low- and high-grade squamous intraepithelial lesions (LSIL, HSIL), is not completely clear. Co-infections could act in cervical microenvironment by several mechanisms, such as direct genotoxicity, induction of inflammation, leading to reactive oxidative metabolites generation and decrease in cellmediated immunity, which seems to play important roles in the initiation and progression to cervical cancer. These free radicals damage the DNA and DNA repair proteins and inhibit apoptosis, leading to genetic instability. Moreover, the inflammatory cells produce cytokines, chemokines, growth and angiogenic factors, which stimulate the tumour growth [5, 25, 26]. CT has been widely studied as a potential HPV cofactor (Fig. 1), due to concomitant infection and similar form of transmission, asymptomatic nature, and persistence if untreated [3]. CT infection may function as entryway, allowing the access of HPV to basal epithelium layer [3, 6, 27]. Chlamydia can induce chronic inflammation [28], cervical hypertrophy [13, 14] and squamous metaplasia, being metaplastic cells a potential target cells for HPV [3]. These biological effects increase the risk of cervical cells transformation, persistently infected with high-risk HPV types [10, 27]. Also, this could lead to HPV viral load enhancing, genome integration, inhibition of apoptosis, E6/ E7 oncogenes overexpression and cell transformation— genomic instability [3, 6]. CT is a recognized cause of cervicitis [3] and high rates of cervical cancer often overlap with prevalent cervicitis [29]. Rasmussen et al. [30] observed that cervical carcinoma cell lines infected with CT secrete more proinflammatory cytokines than primary uninfected control cervical cells, suggesting that coinfection of HPV and CT induces a pro-inflammatory environment when compared to cervical CT infection. In Portugal, 4.6 % of 1,108 women, aged between 14 and 30 years, were positive for CT infection [31]. Additionally, alterations in cervix were associated with a higher prevalence of infection, (7.3 versus 3.7 %; p = 0.0106). CT-related cervicitis and/or infection of endocervical cells of transformation zone may predispose women to HPV infection by epithelial integrity alteration [3, 27]. Both CT and HPV infections may increase the Ki67 expression, a cell proliferation marker of cervical epithelium. Furthermore, chlamydia enhances HPV16 protein expression in lowgrade squamous lesions (LSIL), suggesting that virus activity could be modified by CT infection [32]. CT modulates host immune response and inhibits apoptosis

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Fig. 1 Hypothetical association between CT/HPV synergic effect and infected host characteristics on the development of cervical carcinogenesis

[33]. Antibody response to chlamydial HSP60 has been considered a marker of persistent infection [3]. Felice et al. [34] proposed that CT HSP60 may interfere with host apoptosis and senescence pathways, leading to active proliferation of damaged cells infected by high-risk HPV types. Paavonen et al. [35] verified that anti-chlamydial HSP60 was associated with an increased risk of CC. CT evading strategies of host defence mechanism of interferon are based on tryptophan biosynthesis and allelic variation of their major surface proteins [5]. Additionally, chlamydial products may also stimulate HPV persistence by the functional decrease in antigen-presenting cells, as well as inhibition of cell-mediated immunity [25]. Although in vitro studies refer that CT induces genetic damage and neoplastic changes, the molecular mechanisms underlying HPV-related cervical carcinogenesis which may be enhanced by CT are not fully understood. Studies of CT prevalence in HPV-associated lesions Previous studies reported an association between antibodies to CT and CC or precursor lesions [7, 10, 35–45]. Two large seroepidemiologic investigations showed highly significant associations between CT seroantibodies and CC [39, 40]. Koskela et al. [39] observed that 30 % of 149 cervical squamous cell carcinoma (SCC) cases compared with 13 % of 442 controls were seropositive for CT at baseline. Serum antibodies to CT were associated with a highest risk for SCC (OR 2.2, 95 % CI 1.3–3.5). The authors also suggested a possible association between CT

serovar and risk for cervical neoplasia [39]. The International Agency for Research on Cancer (IARC) study found an increased prevalence of CT in 1,139 SCC cases compared to a control group of 1,100 women with normal cytology (53 versus 31 %); this association was stronger with increased CT antibody titre [40]. The risk of ICC was higher in CT seropositive women (OR 1.8, 95 % CI 1.2–2.7); CT antibodies were neither associated with adenocarcinoma (ADC) nor adenosquamous carcinoma (OR 1.0, 95 % CI 0.53–1.9) [40]. Madeleine et al. [43] in a population-based study of 302 ICC cases, 185 ADC and 318 HPV seropositive control women, observed a correlation between CT antibodies and risk for SCC (OR 1.6, 95 % CI 1.1–2.2), but not for ADC (OR 1.0, 95 % CI 0.6–1.5). Additionally, CT is not present in cervical ADC, according to reported data of Quint et al. [46], but it may have local immune consequence in the upper genital tract, allowing HPV18 and/or 45 related cell transformation during cervical carcinogenesis. In this study, none of the ADC cases was positive for CT [46]. Luostarinen et al. [47] in a cohort study observed very high relative risk (RR) of CIN3 for concomitant CT and high-risk HPV 18 and 45 seroconversions (RR 28, 95 % CI 4.3–190) compared to HPV 18 and 45 and CT seropositives at baseline. Two cross-sectional studies of Bosch et al. [48] and Mun˜oz et al. [49] showed a significant association between CT antibodies in husband of women with CIN3 or CC. The serotypes D to K of CT are mainly associated with STIs [3]. Anttila et al. [42] reported a possible association between CT serovar and risk for CC, being serotype G


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mostly associated with consequent development of cervical neoplasia. Madeleine et al. [43] also verified an association between specific serotypes of CT and SCC: B (OR 3.6, 95 % CI 1.5–8.4), D (OR 2.1, 95 % CI 1.2–3.5), E (OR 2.4, 95 % CI 1.4–3.9), G (OR 3.0, 95 % CI 1.1–7.9), I (OR 4.2, 95 % CI 1.5–11.7), and J (OR 2.3, 95 % CI 1.0–5.1), but not for C, F, H, and K serotypes with a low prevalence in the study population. This association was not reported by

Smith et al. [40]. On the other hand, some studies did not reveal a significant association between CT antibodies and cervical premalignancy or CC [50–55]. Several studies [6, 19, 27, 56–61] supported an association between CT DNA and HPV infection, cervical neoplasia and/or CC. Additionally, in numerous studies, the prevalence of CT DNA was found to be increased in HPVpositive than HPV-negative samples [57, 59, 62–67]

Fig. 2 a Graphic representation of approximated CT DNA prevalence (%), in HPV-positive samples, cervical neoplasia and/or ICC. CC incidence data were collected from online information on GLOBOCAN [71]. N. Am. Northern America, C. Am. Central America, S. Am. Southern America, N. Eur. Northern Europe, W. Eur. Western Europe, S. Eur. Southern Europe, W. As. Western Asia, CCI cervical cancer incidence. b Graphic representation of

approximated CT DNA prevalence (%) in HPV-negative/control samples. CC incidence data were collected from online information on GLOBOCAN [71]. N. Am. Northern America, C. Am. Central America, S. Am. Southern America, N. Eur. Northern Europe, W. Eur. Western Europe, S. Eur. Southern Europe, W. As. Western Asia, CCI cervical cancer incidence


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(Fig. 2a, b). Lehtinen and colleagues [58] suggested that CT status may be involved in early stages of cervical carcinogenesis. C. trachomatis were associated with CIN2 among women with (HR 1.82, 95 % CI 1.06–3.14) and without HPV 16/18 infection (HR 1.74, 95 % CI 1.05–2.90). No increased risk related with CT was found for CIN3 or worse [58]. A cross-sectional study showed that CT DNA was related with a higher risk of both lowand high-grade squamous intraepithelial lesions (LSIL, OR 5.1, 95 % CI 1.4–19; HSIL, OR 5.8, 95 % CI 1.5–22, respectively), but not with ICC (OR 2.1, 95 % CI 0.36–12) [57]. Giuliano et al. [68] in a cross-sectional study did not find an association between CT DNA and HSIL. On the other hand, previous studies of Giuliano et al. [59, 60] reported an association between HPV detection and CT DNA after adjustment for sexual behaviour. Wallin et al. [56] in a population-based prospective study showed that past chlamydial infection was related with an increased risk for ICC (OR 17.1, 95 % CI 2.6–?). Some data support an association between CT infection and increased HPV persistence. Molano et al. [66] in a cross-sectional study observed that women with any multiple HPV infections had an increased risk of concurrent infection with CT (adjusted OR 2.5, 95 % CI 1.1–5.9). Paba et al. [6] analysed CT DNA in 149 CC and CIN biopsies. Detection of CT was significantly (p = 0.0001) associated with multiple HPV infections, increasing the risk of two HPV genotypes (OR 7.27, 95 % CI 2.51–20.83). A cohort study of female adolescents reported that concomitant infection with CT was independently associated with high-risk HPV types persistence (adjusted OR 2.1, 95 % CI 1.0–4.1) [27]. However, those findings were not supported by several other studies but not all of them [52, 68–70]. CC is the third most common cancer and the seventh overall, with an estimated 529,000 new cases in 2008. High-risk regions include Eastern and Western Africa, with a cumulative risk of 3.8 %, Southern Africa (2.9 %), South-Central Asia (2.6 %), Middle Africa and South America (2.5 %). Low-risk areas included Western Asia, Northern America and Australia/New Zealand [4]. Figures 2a and 3a represent several epidemiological studies on CT DNA and seroprevalence, detected in HPV-positive specimens, CIN 1, 2 and 3, HSIL, ICC and ADC. Exposure to CT, measured by DNA positivity, is an indicator of current infection, while CT seropositivity is an indicator of past infection. CT seroprevalence and DNA vary upon study population and design, sample size, detection methods and geographic localization. Several countries have implemented screening programs for HPV, CT and other STIs to reduce related harmfully outcomes [3]. There was no linear association between CC incidence and CT DNA/ seroprevalence (Figs. 2a, 3a), but synergic interaction between CT and HPV in cervical carcinogenesis remains

possible, since intraepithelial neoplasia is related to chronic inflammation. CT DNA and seroprevalence are decreased in HPV-negative samples and control used in the studies referred to throughout this review (Figs. 2b, 3b). Figures 2b and 3b depict the results of several studies on CT DNA and seroprevalence analysed in HPV-negative samples and/or control population. Although the controversy in CT/HPV association, there is some biological plausibility concerning concomitant infection by these sexually transmitted agents. CC incidence data were collected from online information on GLOBOCAN [71]. Briefly, CT may exert its effect (1) in cervical epithelium; function as entryway, allowing the access of HPV to basal epithelium layer, and enhancing HPV viral load; (2) interacts with high-risk HPV types; and (3) modulate the host immune response, inhibiting the apoptosis process [3, 6]. The multistage process of cervical HPV-associated carcinogenesis, which may be affected by CT, is not entirely elucidated. This highlights the prevention usefulness of both HPV and CT infections, aiming to reduce cervical cancer rate and CT-related gynaecological complications in women of reproductive age. Overall, the data reported to date provide initial evidence of a possible epidemiological association between CT and HPV in CC.

Concluding remarks Although many women are infected with high-risk types of HPV, only a subset will ever develop CC, suggesting that other cofactors must be mechanistically present on development of malignancy. The specific question of the multistage process of HPV-related carcinogenesis which may be synergistically affected by CT has not been entirely elucidated and several viewpoints remain uncertain. We speculate that the inflammatory response and metaplasia caused by CT infection may promote cell turnover that are needed for HPV replication and productive cycle. Persistent CT infections may induce an inflammatory milieu advantageous to HPV-related carcinogenesis by increasing the risk of DNA replication errors and active proliferation of genetically damaged cells. Confirmatory studies evaluating the exact cause/effect of CT and HPV infection in the cervical microenvironment, which influences the outcome of the infection, are needed. Further studies based on larger cohorts with longitudinal follow-up in relation to the CT acquisition and thorough evaluation of temporal relationships of concomitant infection with high-risk HPV types/ CT and cervical neoplasia are needed to demonstrate whether or not CT infection could change the proportion of permissive cells to high-risk HPV types; whether and how in some cases CT sets the natural history of HPV infection, HPV persistence and progression to premalignant


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Fig. 3 a Representation of approximated CT seroprevalence in in HPV-positive samples, CIN 1, 2, 3, HSIL, ICC, and ADC. CC incidence data were collected from online information on GLOBOCAN [71]. N. Am. Northern America, C. Am. Central America, S. Am. Southern America, N. Eur. Northern Europe, S. Eur. Southern Europe, E. AS. East Asia, SE. As. Southeast Asia, CCI cervical cancer

incidence. b Representation of approximated CT seroprevalence in in HPV-negative/control specimens. CC incidence data were collected from online information on GLOBOCAN [71]. N. Am. Northern America, C. Am. Central America, S. Am. Southern America, N. Eur. Northern Europe, S. Eur. Southern Europe, E. AS. East Asia, SE. As. Southeast Asia, CCI cervical cancer incidence

phenotype or viral clearance, and how this bacterium sets the stage for cervical carcinogenesis. Methodological issues, such as specimen collection and sensitive detections assays, should be evaluated to enhance the success of epidemiologic studies. Screening programmes remain important to identify asymptomatic cases for treatment and limit reproductive complications. Our review points to possible association between HPV and CT infections and

incidence of ICC by inducing the pro-inflammatory mediators’ expression, altering cell to cell adhesion, and affecting cell differentiation. In a public health approach, prevention and control of STIs should foment safer sexual behaviour, incite early health care-seeking, and introduce prevention and care activities across all primary health care providers. Early detection and treatment of uncomplicated chlamydial lower genital tract infections may reduce the


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morbidity rates, and possibly decrease the HPV infection and ICC incidence rate. Conflict of interest authors.

There are no conflicts of interest for any of the

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Chlamydia trachomatis infection: implications for HPV status and cervical cancer.

Genital Chlamydia trachomatis (CT) infections have been identified as a major health problem concern. CT is associated with adverse effect on women re...
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