Prevalence of plasmid-bearing and plasmid-free Chlamydia trachomatis infection among women who visited obstetrics and gynecology clinics in Malaysia
© Yeow et al. 2016
Received: 4 June 2015
Accepted: 10 March 2016
Published: 18 March 2016
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The 7.5 kb cryptic plasmid of Chlamydia trachomatis has been shown to be a virulence factor in animal models, but its significance in humans still remains unknown. The aim of this study was to investigate the prevalence and potential involvement of the C. trachomatis cryptic plasmid in causing various clinical manifestations; including infertility, reproductive tract disintegrity, menstrual disorder, and polycystic ovarian syndrome (PCOS) among genital C. trachomatis–infected patients.
A total of 180 female patients of child bearing age (mean 30.9 years old, IQR:27–35) with gynecological complications and subfertility issues, who visited Obstetrics and Gynecology clinics in Kuala Lumpur, Malaysia were recruited for the study. Prevalence of genital chlamydial infection among these patients was alarmingly high at 51.1 % (92/180). Of the 92 chlamydia-infected patients, 93.5 % (86/92) were infected with plasmid-bearing (+) C. trachomatis while the remaining 6.5 % (6/92) were caused by the plasmid-free (−) variant. Our data showed that genital C. trachomatis infection was associated with infertility issues, inflammation in the reproductive tract (mucopurulent cervicitis or endometriosis), irregular menstrual cycles and polycystic ovarian syndrome (PCOS). However, no statistical significance was detected among patients with plasmid (+) versus plasmid (−) C. trachomatis infection. Interestingly, plasmid (+) C. trachomatis was detected in all patients with PCOS, and the plasmid copy numbers were significantly higher among PCOS patients, relative to non-PCOS patients.
Our findings show a high incidence of C. trachomatis infection among women with infertility or gynecological problems in Malaysia. However, due to the low number of plasmid (−) C. trachomatis cases, a significant role of the plasmid in causing virulence in human requires further investigation of a larger cohort.
KeywordsChlamydia trachomatis Reproductive system disorders Infertility Plasmid
In recent years, several research groups suggest that the C. trachomatis without plasmid demonstrates a weaker degree of virulence. The plasmid-deficient strains show impaired ability to infect the female mouse genital tract [9, 10]. C. trachomatis infection damages the reproductive tract by activating TLR2 and initiates a Th1-dependent inflammatory response. In a study using plasmid-cured C. muridarum mutant infection in a murine model, TLR2-dependent cytokine was not detected and no sign of oviduct damage can be observed, suggesting that the plasmid-cured mutant has lost virulence . Also, intra-vaginal immunization of the plasmid-deficient strains provide protection in the murine model of genitourinary tract infection ; as well as in trachoma infected macaques  due to the failure to trigger a Toll-like receptor 2-dependent immune response . These findings have led to research on use of plasmid-deficient strains as a potential human vaccine. In fact, an intravaginal infection of attenuated plasmidless C. trachomatis L2 has been shown to provide protection to the host because it is nonpathogenic and raises systemic antibody in the C3H/HeJ mouse model .
Despite compelling evidence in animal models, there is no equivalent finding from human clinical study confirming the significance of plasmid in C. trachomatis infection. A recent study in human ocular C. trachomatis infection reveals that no direct association exists between plasmid copy numbers and disease severity . Therefore, further work should be done to establish the plausible connection. In this study, we investigated the prevalence of plasmid-bearing (+) or plasmid-free (−) C. trachomatis infection and the plasmid copy numbers among obstetrics and gynecology patients in Kuala Lumpur, the capital city of Malaysia. By associating the data with the patients’ clinical presentations, we evaluated the prevalence and risk of plasmid (+) and plasmid (−) variants in affecting gynecological disorders.
Demographics of the study population
Patient demographics. Numbers (percentages) of patients with or without C. trachomatis infection; and patients infected with plasmid (−) or plasmid (+) variants. n = 180. The P values for all variables were measured with Fisher’s exact test. For age, a t-test (a) was used. n.s.: non-significant
(n = 180)
(n = 88)
C. trachomatis infection
(n = 92)
(95 % CI)
(n = 6)
(n = 86)
(95 % CI)
0.60 n.s. a
0.59 n.s. a
124 (68.8 %)
55 (44.4 %)
69 (55.6 %)
3 (4.3 %)
66 (95.6 %)
12 (6.7 %)
6 (50 %)
6 (50 %)
0 (0 %)
6 (100 %)
1 (0.5 %)
0 (0 %)
1 (100 %)
0 (0 %)
1 (100 %)
43 (23.8 %)
27 (62.7 %)
16 (37.3 %)
3 (18.7 %)
13 (81.2 %)
123 (68.3 %)
64 (52.1 %)
59 (47.9 %)
4 (6.7 %)
55 (93.2 %)
24 (13.3 %)
11 (45.9 %)
13 (54.1 %)
1 (7.6 %)
12 (92.3 %)
23 (12.7 %)
10 (43.5 %)
13 (56.5 %)
1 (7.6 %)
12 (92.3 %)
10 (5.5 %)
3 (30 %)
7 (70 %)
2.333 (0.58 to 9.32)
0 (0.0 %)
7 (100.0 %)
C. trachomatis infection is associated with various gynecological disorders
Chlamydial infection in patients with different symptoms. Numbers (percentages) of patients with or without C. trachomatis infection. n = 180. The P values for all variables were measured with Fisher’s exact test. n.s.: non-significant
All patients (n = 180)
Non-infected (n = 88)
-infected (n = 92)
Odd Ratio (95 % CI)
76 (67.9 %)
36 (32.1 %)
12 (17.6 %)
56 (82.4 %)
9.852 (4.70 to 20.63)
- 1° or 2° infertility
4 (9.3 %)
39 (90.7 %)
20.580 (6.83 to 62.02)
8 (32.0 %)
17 (68.0 %)
4.486 (1.77 to 11.36)
79 (55.2 %)
64 (44.8 %)
9 (24.3 %)
28 (75.7 %)
3.84 (1.69 to 8.72)
- Mucopurulent Cervicitis
9 (36.0 %)
16 (64.0 %)
2.167 (0.90 to 5.23)
0 (0.0 %)
12 (100.0 %)
30.43 (1.77 to 524.2)
70 (53.8 %)
60 (46.2 %)
18 (36.0 %)
32 (64.0 %)
2.074 (1.05 to 4.06)
87 (51.2 %)
83 (48.8 %)
1 (10.0 %)
9 (90.0 %)
9.434 (1.17 to 76.14)
Overall, C. trachomatis infection showed an association with infertility (OR:9.85, 95 % CI:4.70–20.63, P < 0.0001***) (Table 2). Among patients who were fertile, only 32.1 % (36/112) were infected by C. trachomatis, whereas among infertile patients, 82.4 % (56/68) had C. trachomatis infection. Notably, a high C. trachomatis prevalence of 90.7 % (39/43,) was detected among patients who were diagnosed with primary (1°) or secondary (2°) infertility (OR:20.580, 95 % CI:6.83–62.02, P < 0.0001***). Meanwhile, 68 % (17/25) of patients who experienced miscarriage were infected by C. trachomatis (OR:4.486, 95 % CI:1.77–11.36, P = 0.0013**).
The inflammation (cervicitis with mucopurulent discharge or endometriosis) of patients’ reproductive tract was recorded by clinicians during examination. C. trachomatis infection showed a close connection with the inflammation in the reproductive system (OR:3.84, 95 % CI:1.69–8.72, P = 0.0008***) (Table 2). Our data showed that approximately 64 % (16/25) of patients who were diagnosed with mucopurulent cervicitis (OR:2.167, 95 % CI:0.90–5.23, P = 0.087) and 100 % (12/12) of patients with endometriosis (OR:30.43, 95 % CI:1.77–524.2, P < 0.0001***) had C. trachomatis infection.
In addition, we showed that C. trachomatis infection exhibited significant association with irregular menstrual cycles (OR:2.07, 95 % CI:1.05–4.06, P = 0.045*) as well as PCOS (OR:9.43, 95 % CI:1.17–76.14, P = 0.018*), when compared to the uninfected controls.
Higher incidence of plasmid-bearing C. trachomatis infection among patients with infertility, inflammation and PCOS
Next, we investigated if the patients enrolled were infected by plasmid (+) or (−) C. trachomatis variants. Total DNA extracted from the vaginal swabs of the C. trachomatis-infected patients were amplified with two sets of cryptic plasmid primers (which target Pgp1 and Pgp8 respectively) using quantitative real-time PCR analysis. Of the 92 C. trachomatis-infected patients, we detected that 93.5 % (86/92) were caused by plasmid (+) C. trachomatis whereas only 6.5 % (6/92) were caused by plasmid (−) C. trachomatis (Table 1).
C. trachomatis plasmid in patients with different symptoms. Numbers (percentages) of patients infected with plasmid (−) or plasmid (+) C. trachomatis variants. n = 92. The P values for all variables were measured with Fisher’s exact test. n.s.: non-significant
C. trachomatis-infected patients (n = 92)
Plasmid (−) C. trachomatis (n = 6)
Plasmid (+) C. trachomatis (n = 86)
Odd Ratio (95 % CI)
2 (5.55 %)
34 (94.4 %)
4 (7.14 %)
52 (92.8 %)
0.764 (0.13 to 4.40)
- 1° or 2° infertility
3 (7.6 %)
36 (92.3 %)
0.755 (0.14 to 3.95)
1 (5.8 %)
16 (88.2 %)
0.875 (0.09 to 8.01)
5 (7.8 %)
59 (92.1 %)
1 (3.5 %)
27 (96.4 %)
2.288 (0.25 to 20.55)
- Mucopurulent Cervicitis
0 (0.0 %)
16 (100 %)
5.269 (0.28 to 98.68)
1 (8.3 %)
11 (91.6 %)
0.733 (0.078 to 6.88)
5 (8.3 %)
55 (91.6 %)
1 (3.1 %)
31 (96.8 %)
2.818 (0.31 to 25.24)
6 (72.2 %)
77 (92.7 %)
0 (0 %)
9 (100 %)
1.59 (0.083 to 30.6)
Higher relative plasmid copy numbers associated with PCOS
To examine if the abundance of plasmid in C. trachomatis is associated with the presence of the clinical symptoms, we quantified the plasmid copy numbers in each patient (Figure 1). The average CT value from two cryptic plasmid primers (Pgp1 and Pgp8) for each patient was obtained. Relative plasmid copy numbers per bacterium (ratio for plasmid:Momp) for all 92 C. trachomatis-infected patients were calculated. In general, we noticed no direct connection between fertility, the reproductive tract lining and menstrual cycle, consistent with the previous studies in human ocular infection and in vitro tissue tropism [14, 17]. Notably, PCOS patients showed a higher plasmid copy number (2.386 ± 0.284 versus 1.734 ± 0.096, P = 0.0472), relative to the non-PCOS patients. Although endometriosis patients also demonstrated a comparatively higher plasmid copy number, (2.193 ± 0.308 versus 1.714 ± 0.110, P = 0.114), no statistical significance was noted.
In this study, we reported a high prevalence (51.1 %) of C. trachomatis infection among female adults of child bearing age, with subfertility or gynecological problems who visited Obstetrics and Gynecology clinics in Malaysia. This indicates that there is a pressing need for wider population screening to increase awareness and prevent the spread of the disease among the community. Most of the patients who demonstrated symptoms were diagnosed with genital C. trachomatis infection, including infertility (82.4 %), reproductive system lesions (75.7 %), irregular menses (64 %) and PCOS (90 %), suggesting the C. trachomatis is a leading factor for female reproductive system disorders.
Although a high rate of genital C. trachomatis prevalance was detected in our study, the patients recruited were suspected to be at risk of the bacterial infection based on the clinical examination. The rates of C. trachomatis infection vary in different studies depending on the group of patients recruited and the study region. For example, a study using 50 infertile female patients showed a 40 % infection rate by C. trachomatis  whereas other studies reported only a 8 %  or 15 % C. trachomatis infection rate. Among patients with tubal infertility, the prevalence of C. trachomatis was reported to be 38.3 % among 120 patients . Consistent to the previous study, the presence of plasmid (+) C. trachomatis was high (93.5 %). However, the prevalence using real-time PCR amplification depends highly on the assay sensitivity. For data validation, a glycogen-positive test for bacterial isolates can be used to confirm the presence of plasmid in the bacteria .
Various research groups have established that the plasmid (+) C. trachomatis demonstrated a higher virulence in animal models of ocular or genital infections [9–14]. Consistent with these findings, our results showed that high percentages of those who had infertility (92.8 %), inflammation in the reproductive tract (96.4 %), irregular menses (96.8 %) and PCOS (100 %) were diagnosed with plasmid (+) but not plasmid (−) variants of C. trachomatis. Although these observations provide support for previous work which suggests the usage of plasmidless C. trachomatis as a potential human vaccine , caution must be taken as some of the patients who showed symptoms were infected by the plasmid (−) strains. Also note that the genetic diversity of human populations may contribute to results contradicting experiments performed using inbred animals. Therefore, additional surveys which involve a larger human cohort should be conducted to ensure the over-all safety of the plasmidless strains among individuals from diverse backgrounds.
Plasmid (+) or (−) C. trachomatis strains demonstrated no difference with regards to growth kinetics, plaquing efficiency and size but showed a defect in glycogen granule accumulation and intrainclusion movement . A recent study showed that C. trachomatis is capable of inducing alteration to global host histone modifications and double strand break repair, thus generating an environment favorable for malignant transformation . In fact, C. trachomatis infection poses risk for infected individuals to develop cervix intraepithelial neoplasia [23, 24], in a similar way to other tumor-inducing pathogens. Extra-chromosomal plasmid DNA may play a role in integrating with the host genome which leads to this pathological damage. The conserved 7.5 kb cryptic plasmid is a small, non-conjugative and non-integrative extrachromosomal DNA that contains genes encoding 8 proteins . The plasmid Pgp3 encodes for immunogenic trimers which trigger specific antibody production in infected individuals [26, 27]; and is secreted into the cytosol of infected cells during chlamydial infection [28, 29]. Meanwhile, Pgp4 encodes for a protein which comprises a putative helix-loop-helix domain which functions as transcriptional regulator for virulence-associated genes [10, 30]. Therefore, expression of plasmid genes may be crucial in leading to clinical symptoms. To support this notion, a quantitative protein analysis could be carried out in the future to measure the amount of plasmid-derived proteins in the patient sample.
In conclusion, we suggest that plasmids maybe a potential risk factor for reproductive system disorders including infertility, inflammation in the reproductive tract, irregular menses and PCOS in genital chlamydial infection. However, continued work is required to substantiate plasmids as a virulence factor in future studies with a larger human cohort.
A total number of 180 female patients of child-bearing age who visited the Obstetrics and Gynecology Outpatient Clinics at the University of Malaya Medical Centre voluntarily participated in the study from 2010 to 2014. Detailed clinical information on reasons for referral, gynecological history including menstruation, symptoms of genital and urinary tract infection, obstetric and medical histories were documented. The subjects’ vulva and cervix were examined for the presence of lesions, warts, ulcers, ectopy, erythma and discharge. Patients with a positive urine pregnancy test, recent antibiotic therapy, yeast infection and genital tuberculosis were excluded from the study. The participants were briefed that their blood and vaginal swab samples will be used for research purposes, and written consent was obtained. This study has been approved by the University of Malaya Medical Centre Medical Ethics Committee.
Endocervical swabs were collected by using a Floqswab (Copan, Brescia, Italy) and transferred to a laboratory in a UTM-RT universal transport medium tube (Copan). The samples were vortex mixed and the cells were centrifuged at 400× g for 10 min. The cells recovered were lysed and separated with phenol chloroform. The DNA was precipitated using 1:10 volume of 3 M sodium acetate and isopropanol at −20 °C overnight incubation. The samples were washed and eluted with TE buffer.
PCR primers used in C. trachomatis conventional PCR and real-time PCR diagnosis. For nested PCR amplification of Momp and plasmid, outer primer pairs were used at first round PCR, while inner primer pairs were used at second round PCR amplification. For real-time PCR diagnosis, Momp inner primer pairs, plasmid Pgp8 inner primer pairs and plasmid Pgp1 primer pairs were used
Quantitative real-time PCR amplification
Amplification of an approximately 871 bp fragment of OmpA was performed by nested PCR. The first PCR step was carried out with outer primer pair (Table 1) using 10 μl of DNA extracted from swabs. Amplification was performed in a final reaction volume of 50 μl containing 0.3 μM of each primer, 0.2 mM of dNTPs, 3 μl of TuneUp solution (Nanohelix, Korea) and 5U of HelixAmp™Taq DNA polymerase (Nanohelix, Korea). The first amplification conditions consisted of initial polymerase activation at 94 °C for 2 min; 40 cycles of 94 °C for 45 s, 60 °C for 45 s and 72 °C for 90 s and a final elongation step at 72 °C for 5 min. In the second round PCR, 3 μl of product from the first PCR step was amplified using inner primer pairs (Table 1). Nested PCR conditions consisted of 95 °C for 5 min; 40 cycles of 94 °C for 1 min, 60 °C for 1 min and 72 °C for 2 min and a final elongation step at 72 °C for 10 min. The amplified products were visualized by electrophoresis on 1.5 % agarose gel stained with GelRed solution (Biotium).
The 871 bp OmpA fragments obtained were purified using a QIAquick Gel Extraction kit (Qiagen) and processed using a BigDye® Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems, Foster City, CA). The reaction mixtures were loaded onto a 3730xL DNA Analyzers (Applied Biosystems). The primers used for sequencing were inner primer pairs. Nucleotide sequence data were assembled by Bioedit and residues corresponding to flanking primers were excluded from analysis. Sequences were submitted to the standard nucleotide BLAST search engine at the National Center for Biotechnology Information (blast.ncbi.nlm.nih.gov/Blast.cgi) to determine the genotype.
Statistical analysis was done using GraphPad PRISM version 5. For normally distributed data, an unpaired t-test was used. For categorical data (clinical symptoms), Fisher’s exact test was used, with a no-symptom group as control. Odd ratio (OR) and 95 % confidence interval (CI) were calculated. Statistical significance was determined at P < 0.05*, P < 0.01** and P < 0.001***.
Availability of data and materials
All data and materials are available upon request.
Major outer membrane protein
polycystic ovary syndrome
pelvic inflammatory disease
sexually transmitted disease
The authors would like to thank the volunteers and nurses at the University of Malaya Medical Center Obstetrics and Gynecology clinics for their assistance in sample collection. This study was supported by grants from Malaysia Ministry of Higher Education (HIR-MOHE E000013-20001) to WFW and Fundamental Research Grant Scheme (FRGS) FP027-2010B to NSS.
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