The Combination of the Gastrointestinal Integrin (α4β7) and Selectin Ligand Enhances T-Cell Migration to the Reproductive Tract During Infection with Chlamydia trachomatis

Problem  Chlamydia trachomatis causes sexually transmitted infection and reproductive dysfunction worldwide. Identifying a population of endocervical T-cells to target in vaccine development is likely to enhance efficacy of a vaccine and reduce reproductive tract dysfunction.
Method of study  Endocervical samples were obtained from young women and flow cytometric analysis was used to identify lymphocytes that appeared in the genital tract in response to sexually transmitted bacterial infections caused by C. trachomatis.
Results  Increased numbers of α4β7+CLA+ memory T-cells, a unique T-cell phenotype, were found in the endocervix of human female subjects infected with C. trachomatis .
Conclusion A unique population of memory T lymphocytes expressing both α4β7 and CLA gain access to reproductive tract tissues during a sexually transmitted infection with C. trachomatis and should be considered in development of vaccines against sexually transmitted infections.     

Cross sectional study to evaluate microbiological spectrum of RTI/STI and co-infections among women with cervicitis or cervico-vaginitis from a community clinic in Mumbai

Cervicitis is an inflammatory condition of cervix, when presented along with vaginal discharge; it is termed as cervico-vaginitis. These can be infective, hence important to diagnose due to risk of spreading to upper genital tract. This cross-sectional study was undertaken to evaluate the microbiological spectrum in cervicitis or cervico-vaginitis among 100 sexually active women by Gram stain and Multiplex Real time polymerase chain reaction. Bacterial vaginosis 21(21%) was the most common RTI. Among STIs, genital mycoplasmas were the predominant infections hence further research is required to understand their pathogenesis.     

Chlamydia trachomatis in subfertile women undergoing uterine instrumentation. The clinician's role

Most women attending a fertility clinic will undergo uterine instrumentation either diagnostically and/or therapeutically. This places them at potential risk of chlamydial pelvic inflammatory disease. Clinicians remain unclear about the roles of screening, serology and prophylactic antibiotics. A review of the evidence suggests that women <25 years and those older with risk factors, men with risk factors and gamete donors should have their lower genital tract screened for Chlamydia trachomatis by a sensitive test. More information is required before screening men by age can be recommended. Serology in its present form cannot be advocated as a screening tool. Those women with a past history of chlamydial morbidity or a diagnosis of tubal pathology should, in addition to screening, be covered with prophylactic antibiotics when undergoing uterine instrumentation. The partner should be screened for sexually transmitted infections. Non-selective use of prophylactic antibiotics serves only to increase the problem of antibiotic resistance and maintain the bacterial load of chlamydia in the community.     

Community-based study on seroprevalence of herpes simplex virus type 2 infection in New Delhi

PURPOSE: To determine the seroprevalence of herpes simplex virus type 2 (HSV-2) in two urban communities in Delhi and to correlate the presence of HSV-2 seroprevalence with sociodemographic profile, risk factors and presence of other reproductive tract infections (RTIs). METHODS: Men and women aged between 15-49 years from an urban slum and an urban middle class colony were invited to participate in the study. They provided interview information; blood for HSV-2, HIV and syphilis serology; first void urine specimens for diagnosis of Neisseria gonorrhoeae and Chlamydia trachomatis infection; and genital specimens for diagnosis of bacterial vaginosis, vaginal candidiasis and trichomoniasis. RESULTS: The prevalence of HSV-2 seropositivity was found to be 7 and 8.6% in men and women, respectively. HSV-2 seropositivity was found to be significantly associated with urban middle class community and older age. No statistically significant correlation was found between HSV-2 seropositivity and other laboratory-confirmed RTIs. CONCLUSIONS: The findings of our study indicate a relatively low prevalence of HSV-2 seropositivity and other sexually transmitted infections in the two communities that were studied.     

Chlamydia trachomatis: impact on human reproduction

Chlamydia trachomatis infections are the most prevalent bacterial sexually transmitted infections (STI) recognized throughout the world. Worldwide, the magnitude of morbidity associated with sexually transmitted chlamydial infections is enormous. C.trachomatis is a common cause of urethritis and cervicitis, and sequelae include pelvic inflammatory disease (PID), ectopic pregnancy, tubal factor infertility, epididymitis, proctitis and reactive arthritis. The sharp worldwide increase in the incidence of PID during the past two decades has led to the secondary epidemics of tubal factor infertility and ectopic pregnancy. Chlamydial PID is the most important preventable cause of infertility and adverse pregnancy outcome. Chlamydial infections, like STI in general, are primarily a woman's health care issue since the manifestations and consequences are more damaging to the reproductive health in women than in men. Based on the available evidence, approximately 20% of women with chlamydial lower genital tract infection will develop PID, approximately 4% develop chronic pelvic pain, 3% infertility, and 2% adverse pregnancy outcome. However, these estimates are based on relatively weak evidence. Research on the link between C.trachomatis and male aspects of infertility has been much more limited. Currently recommended treatment regimens include azithromycin in a single dose or doxycycline for 7 days. These therapies are highly efficacious. Timely management of sex partners is essential for decreasing the risk for re-infection. Immunopathogenesis of C.trachomatis infection is one of the main focal points of current research into Chlamydia. Chlamydial infection fills the general prerequisites for disease prevention by screening, i.e. chlamydial infections are highly prevalent, usually asymptomatic, are associated with significant morbidity, can be reliably diagnosed, and are treatable. Screening programmes for C.trachomatis will be of paramount importance in the prevention of long-term sequelae. The cost of screening is only a fraction of the health care costs incurred due to complications resulting from undiagnosed and untreated chlamydial infections. Current strategies to control C.trachomatis still largely depend on clinic-based screening of symptomatic patients, and have not been successful. The development of highly sensitive and specific nucleic acid amplification tests for the diagnosis of chlamydial infections has been an important advance in the ability to conduct population-based screening programmes to prevent complications. Thus, the case for screening is clearly made, but much detail remains to be worked out.     

Reversible deficiency of antimicrobial polypeptides in bacterial vaginosis

Bacterial vaginosis is a common condition associated with increased risk of sexually transmitted diseases, including human immunodeficiency virus infections. In contrast, vulvovaginal candidiasis has a much weaker association with sexually transmitted diseases. We found that vaginal lavage fluid from women with bacterial vaginosis is deficient in antimicrobial polypeptides and antimicrobial activity compared to fluid from healthy women or women with vulvovaginal candidiasis. Effective treatment normalized the concentrations of antimicrobial polypeptides in both bacterial vaginosis and in vulvovaginal candidiasis, suggesting that the abnormalities were a result of the diseases. Unlike in vulvovaginal candidiasis, the neutrophil attractant chemokine interleukin-8 (IL-8) was not increased in bacterial vaginosis, accounting for low concentrations of neutrophil-derived defensins in vaginal fluid. In organotypic cultures of human vaginal epithelium containing dendritic cells, treatment with Lactobacillus jensenii, a typical vaginal resident, induced the synthesis of IL-8 mRNA and the epithelial human beta-defensin-2 mRNA, but a typical bacterial vaginosis pathogen, Gardnerella vaginalis, had no effect. When the two bacteria were combined, Gardnerella vaginalis did not interfere with the immunostimulatory effect of Lactobacillus jensenii. The loss of normal immunostimulatory flora in bacterial vaginosis is thus associated with a local deficiency of multiple innate immune factors, and this deficiency could predispose individuals to sexually transmitted diseases.     

Relationship between female genital tract infections,mucosal interleukin‐17 production and local T helper type 17 cells

T helper type 17 (Th17) cells play an important role in immunity to fungal and bacterial pathogens, although their role in the female genital tract, where exposure to these pathogens is common, is not well understood. We investigated the relationship between female genital tract infections, cervicovaginal interleukin-17 (IL-17) concentrations and Th17 cell frequencies. Forty-two cytokines were measured in cervicovaginal lavages from HIV-uninfected and HIV-infected women. Frequencies of Th17 cells (CD3⁺ CD4⁺ IL-17a⁺) were evaluated in cervical cytobrushes and blood by flow cytometry. Women were screened for Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium, Trichomonas vaginalis and herpes simplex virus 2 by PCR, and candidal infections and bacterial vaginosis by Gram stain. Women with bacterial sexually transmitted infections (STIs), specifically chlamydia and gonorrhoea, had higher genital IL-17 concentrations than women with no STI, whereas women with candidal pseudohyphae/spores had lower IL-17 concentrations compared with women without candidal infections. Viral STIs (herpes simplex virus 2 and HIV) were not associated with significant changes in genital IL-17 concentrations. Genital IL-17 concentrations correlated strongly with other inflammatory cytokines and growth factors. Although Th17 cells were depleted from blood during HIV infection, cervical Th17 cell frequencies were similar in HIV-uninfected and HIV-infected women. Cervical Th17 cell frequencies were also not associated with STIs or candida, although few women had a STI. These findings suggest that IL-17 production in the female genital tract is induced in response to bacterial but not viral STIs. Decreased IL-17 associated with candidal infections suggests that candida may actively suppress IL-17 production or women with dampened IL-17 responses may be more susceptible to candidal outgrowth     

Correlation of local interleukin-1beta levels with specific IgA response against Gardnerella vaginalis cytolysin in women with bacterial vaginosis

PROBLEM: Mucosal immune system activation may represent a critical determinant of adverse sequelae correlated with bacterial vaginosis, as HIV sexual transmission, upper genital tract infections, cervicitis, endometritis, postsurgical infections, and adverse pregnancy outcomes as preterm delivery (PTD), low birth weight (LBW). METHOD OF STUDY: Levels of interleukin-1beta (IL-1beta), anti-Gardnerella vaginalis hemolysin (Gvh) IgA, pH, Nugent score, and number of leukocytes were measured in vaginal fluids of 60 fertile women with bacterial vaginosis and of 64 healthy controls. RESULTS: Vaginal IL-1beta levels were nearly 13-fold higher in women with bacterial vaginosis (BV) and were associated with anti-Gvh IgA response. IL-1beta was positively correlated with leukocyte counts in the smear both in healthy and bacterial vaginosis positive women. CONCLUSIONS: Induction of the proinflammatory cytokine IL-1beta may be a necessary event to elicit an innate immune response to control anaerobic genital tract infections. High levels of vaginal IL-1beta are associated with mounting of an antigen-specific mucosal immune response in women with bacterial vaginosis. Parallel induction of innate and adaptive immune response may be associated with protection from ascent of micro-organisms to the upper genital tract, and from acquiring viral infection through the vaginal tract.     

Vaginal immunity in the HSV-2 mouse model

Herpes simplex virus type 2 (HSV-2) is a sexually transmitted pathogen that infects the genital tract. Efforts to develop vaccines to protect women against this and other sexually transmitted pathogens would be facilitated by a better understanding of the immune mechanisms that protect the female reproductive tract against such infections. Such information would be invaluable in developing vaccine strategies to promote the type and magnitude of immune responses in the genital tract that would effectively protect against infection. This review focuses on recent studies using a progestin-treated adult mouse model to explore mucosal immunity to HSV-2 in the vagina. Evidence indicating a major role for both humoral and T cell immunity is presented.     

VAGINAL IMMUNITY IN THE HSV-2 MOUSE MODEL

Herpes simplex virus type 2 (HSV-2) is a sexually transmitted pathogen that infects the genital tract. Efforts to develop vaccines to protect women against this and other sexually transmitted pathogens would be facilitated by a better understanding of the immune mechanisms that protect the female reproductive tract against such infections. Such information would be invaluable in developing vaccine strategies to promote the type and magnitude of immune responses in the genital tract that would effectively protect against infection. This review focuses on recent studies using a progestin-treated adult mouse model to explore mucosal immunity to HSV-2 in the vagina. Evidence indicating a major role for both humoral and T cell immunity is presented.     

Sexually transmitted diseases in victims of rape

The risk of acquiring a sexually transmitted disease as a result of rape is not known, in part because it is difficult to ascertain whether infections were present before the assault or acquired during it. To investigate this question, we examined female victims of rape within 72 hours of the assault and again at least one week after the assault. Of the 204 girls and women initially examined within 72 hours of the rape, 88 (43 percent) were found to have at least one sexually transmitted disease. These diseases included infections caused by Neisseria gonorrhoeae (6 percent of those tested), cytomegalovirus (8 percent), Chlamydia trachomatis (10 percent), Trichomonas vaginalis (15 percent), herpes simplex virus (2 percent), Treponema pallidum (1 percent), and the human immunodeficiency virus type 1 (HIV-1; 1 percent) and bacterial vaginosis (34 percent). Among the 109 patients (53 percent) who returned for at least one follow-up visit (excluding those who were found to be infected at the first visit or who were treated prophylactically), the incidence of new disease was as follows: gonorrhea, 4 percent (3 of 71); chlamydial infection, 2 percent (1 of 65); trichomoniasis, 12 percent (10 of 81); and bacterial vaginosis, 19 percent (15 of 77). There were no new infections with herpes simplex virus, cytomegalovirus, Trep. pallidum, or HIV-1, but follow-up serologic testing was performed in only 26 percent of the patients. On the basis of our assumptions that most venereal infections present within 72 hours of a rape were preexisting and that new infections identified 1 to 20 weeks later were acquired during the assault, we conclude that the prevalence of preexisting sexually transmitted diseases is high in victims of rape and that they have a lower but substantial additional risk of acquiring such diseases as a result of the assault.     

Hypothesis on the role of sub-clinical bacteria of the endometrium (bacteria endometrialis) in gynaecological and obstetric enigmas.

Unexplained infertility, recurrent abortion, dysfunctional uterine bleeding, pelvic pain, premenstrual syndrome, premature labour, placental insufficiency and pre-eclampsia are examples of common obstetric and gynaecological problems that frequently defy adequate explanation. Bacterial vaginosis, a non-inflammatory condition, is associated with premature labour, but antibiotics administered topically provide less effective prophylaxis than those administered orally. This would indicate that bacterial vaginosis might be a marker for significant genital tract bacteria, but some pathology is dependent on micro-organisms ascending out of reach of topical antibiotics. The author was led to consider the hypothesis that micro-organisms, possibly those associated with bacterial vaginosis, surreptitiously inhabit the uterine cavity (bacteria endometrialis) where they are culprits of some common gynaecological and obstetric enigmas. The objective of this review is to provide an initial theoretical examination of this hypothesis. Bacteria in the endometrium have been associated with infertility. Antiphospholipids have been linked to recurrent miscarriage and pre-eclampsia and with infections including Mycoplasma. Pre-eclampsia might be explained by an exaggerated host response to intrauterine micro-organisms or bacterial toxins. The hypothesis that one common factor, bacteria endometrialis, could provide a plausible explanation for a variety of obstetric and gynaecological mysteries is particularly intriguing. There is sufficient evidence to justify further investigation.     

Reservoir of four organisms associated with bacterial vaginosis suggests lack of sexual transmission.

This study consisted of a search for the possible reservoir and mode of spread of the four bacterial vaginosis-associated organisms Mobiluncus mulieris, Mobiluncus curtisii, Mycoplasma hominis, and Gardnerella vaginalis. Their occurrence in rectal, oral, and pharyngeal specimens from women with and without bacterial vaginosis, their male sexual consorts, four homosexual men, and children (altogether, 374 people) was studied. Genital samples were also obtained from all adults. All four organisms were isolated from the rectums of 45 to 62% of women with bacterial vaginosis and 10 to 14% of women without bacterial vaginosis. They also occurred in the rectums of males and children. M. hominis was recovered from the oropharynxes of 12 adults whose sexual consorts had genital occurrences of the organism. Mobiluncus spp. occurred only in the vaginas of women with bacterial vaginosis (97%). The organisms were only infrequently recovered from genital samples from 135 males. Organisms were recovered from the urethras and/or coronal sulci of 10 of 44 male consorts of women with bacterial vaginosis. However, after 2 weeks of condom use during sexual intercourse, only M. hominis remained in the urethra of one man. These findings suggest that the organisms associated with bacterial vaginosis are not spread sexually but colonize the vagina from an endogenous intestinal tract site. The pathophysiological mechanisms leading to bacterial vaginosis in a subpopulation of all women are still unknown.     

Pelvic inflammatory disease following induced first-trimester abortion. Risk groups, prophylaxis and sequelae

An analysis of published studies of the effect of antibiotic prophylaxis associated with vacuum aspiration abortion includes an examination of risk factors for pelvic inflammatory disease (PID), cervical and vaginal flora present in early pregnancy and in PID, the effect of surgical scrub and of prophylaxis on flora, principles of antibiotic prophylaxis, and economic costs of PID. From several prospective studies, it is clear that nulliparas, women with a history of PID, those bearing Chlamydia trachomatis are at risk of post-abortion infection. No risk was associated with pelvic pain, dysmenorrhea, social class, insertion of an IUD, or timing of resumption of coitus. After an extensive enumeration of microbes found in nonpregnant, pregnant, and PID female genital tracts, it was concluded that only C. trachomatis and N. gonorrheae are clearly associated with PID, while the importance of several other microbes is unclear. Quantitative counts of organisms in any condition are lacking. PID is polymicrobial; different organisms probably account for noniatrogenic PID and post-surgical PID. There is evidence that surgical cleansing of the vagina has no bearing on incidence of post-abortal PID, since the responsible organisms come from the endocervix. 5 controlled clinical trials demonstrated that antibiotic prophylaxis is warranted; that penicillin/ampicillin selectively reduced PID in women with PID history; that imidazoles preferentially reduce PID in the general population without PID history. No lasting side effects or emergence of resistant organisms was reported. The treatment was cost effective, cutting health costs and labor losses 5-8%, and reducing the incidence of spontaneous abortion, secondary infertility, and chronic pain.     

Cytokine expression pattern in the genital tract of Chlamydia trachomatis positive infertile women - implication for T-cell responses

Human genital infection caused by Chlamydia trachomatis is thought to be immunologically mediated, resulting in local recruitment of lymphocyte subsets and inducing the production of cytokines. Little information is available about the role of lymphocyte recruitment and the regulation of cytokine production in the genital tract of C. trachomatis positive infertile women. We have evaluated the recruitment of lymphocyte subsets in the genital tract and production of Th1/Th2 cytokines in cervical secretions and laparoscopic specimens from the fallopian tubes of C. trachomatis positive infertile women (n = 17) and compared them with controls, viz. C. trachomatis negative infertile women (n = 20) using ELISA and flow cytometry. None of these patients were found to be infected either with Candida sps., bacterial vaginosis, Trichomonas vaginalis, Neisseria gonorrhoeae, Mycoplasma hominis or Ureaplasma urealyticum in the cervix. Flow cytometric analysis of cervical secretions in Chlamydia positive women revealed recruitment of both CD4 and CD8 lymphocytes to the genital tract was up-regulated and a variation in the production rates of different cytokines in cervical secretions and fallopian tube was observed. We found that the immune responses in cervical secretions were of Th0 type, since all the analysed cytokines, viz. IFN-gamma, TNF-alpha, IL-10 and IL-12 were up-regulated. As, both CD4 and CD8 cells contribute to the production of IFN-gamma and IL-10, these results suggest that along with CD4 cells, CD8 lymphocytes also may be important for local regulation of Th1/Th2 responses in the genital tract during C. trachomatis infection.     

Tampon sampling for diagnosis of bacterial vaginosis: a potentially useful way to detect genital infections?

Genital tract infections are important causes of ill health in developing countries, but diagnosis is difficult. Bacterial vaginosis (BV) was correctly diagnosed by using a vaginal specimen obtained by tampon sampling in 22 of 24 women (91.6%) for whom BV was diagnosed by Gram staining. The yield for other vaginal infections was higher (28% for Trichomonas vaginalis and 32.7% for Candida albicans) than it was for cervical infections (0% for Neisseria gonorrhoeae and 30% for Chlamydia trachomatis). Tampon sampling was acceptable to patients and may facilitate diagnosis of genital infections in developing countries.     

Seroepidemiologic study of sexually transmitted diseases caused by Chlamydia trachomatis in Casablanca (Morocco)]

Screening 579 sera specimens obtained in Casablanca (Morocco) we have performed a retrospective seroepidemiological survey with regard to the prevalence of Chlamydia trachomatis involved in genital tract infections. The surveyed populations are divided into 3 groups: 177 patients affected with sexually transmitted diseases (STD), 319 reference patients, 83 maghrebian patients affected with STD but living in France. The study was performed by the indirect microimmunofluorescence technique. The prevalence of Chlamydia trachomatis ranging from 50% in the moroccan reference groupe to about 70% among patients with STD both in Morocco and Bordeaux indicates that Chlamydia trachomatis takes a significant part in STD observed in moroccan populations.     

HSV-2 vaccine: Current state and insights into development of a vaccine that targets genital mucosal protection

HSV-2 is one of the most prevalent sexually transmitted infections that result in significant morbidity and financial burden on health systems around the world. Recurrent and asymptomatic re-activation accompanied by viral shedding is common among sero-positive individuals, leading to relatively high efficiency of transmission. Prophylactic HSV-2 vaccines are the best and cheapest option to address the problems associated with HSV-2 infections globally. However, despite persistent efforts, the search for an efficacious vaccine for HSV-2 remains elusive. In this review, the current state of HSV-2 vaccines and the outcome of past human trials are examined. Furthermore, we discuss the evidence and strategies from experimental mouse models that have been successful in inducing protective immunity in the genital tract against HSV-2, following immunization. Future vaccination strategies that focus on induction of robust mucosal immunity in the genital tract may hold the key for a successful vaccine against HSV-2.     

Sialidases (neuraminidases) in bacterial vaginosis and bacterial vaginosis-associated microflora.

Bacterial vaginosis, Prevotella species, and Bacteroides species have been associated with prematurity and upper genital tract infection. Prevotella (Bacteroides) species and Bacteroides fragilis have also been associated with preterm birth. However, the mechanism by which lower genital tract infection causes upper genital tract disease remains poorly understood. Sialidases (neuraminidases) are enzymes which enhance the ability of microorganisms to invade and destroy tissue. Elevated levels of sialidase activity were detected in 42 (84%) of 50 vaginal fluid specimens from women with bacterial vaginosis and none of 19 vaginal fluids from women without bacterial vaginosis (P less than 0.001). Vaginal fluid from women with bacterial vaginosis had a median specific activity of 9.8 U compared to 2.5 U of sialidase in women without bacterial vaginosis (P less than 0.001). In order to determine the probable source of sialidases in vaginal fluid, the microorganisms recovered from women with bacterial vaginosis before and after treatment were assayed. Of 28 specimens from women with bacterial vaginosis, 27 (96%) yielded sialidase-positive bacteria, at a median concentration of 10(6.5) CFU/ml of vaginal fluid. Prevotella and Bacteroides species accounted for the sialidase activity in 26 of the vaginal fluids, and Gardnerella vaginalis accounted for the sialidase activity in the remaining fluid. After treatment, sialidase was detected in the vaginal fluid of 1 (5%) of 22 women who responded to therapy and in all of 6 women for whom therapy failed. These data suggest that vaginal fluid sialidase is highly correlated with bacterial vaginosis and that the probable sources for this enzyme activity are the Bacteroides and Prevotella species present in the vagina.     

Chlamydia trachomatis in subfertile women undergoing uterine instrumentation: an alternative to direct microbial testing or prophylactic antibiotic treatment

Chlamydia trachomatis is the major cause of tubal occlusion, and is also associated with IVF failure and spontaneous abortion. These infections are asymptomatic in most individuals and can persist in the genital tract for long periods of time in a form resistant to immune destruction. A significant percentage of couples seeking treatment for infertility might, therefore, harbour C. trachomatis in their genital tract. An unresolved question is what to do about this possible chlamydial persistence. Cervical, endometrial and semen samples can be tested for C. trachomatis and only positive individuals treated. Alternatively, all couples undergoing infertility treatment can receive prophylactic antibiotics. We advocate a third option, to screen and treat only individuals who are positive for systemic and/or local anti-chlamydial antibody production. Detection of species-specific C. trachomatis antibodies in peripheral blood will determine which individuals have been exposed to this organism and who, therefore, may be at risk for harbouring persistent forms. Identification of IgA antibodies in genital tract secretions may be an even better indicator of the presence of C. trachomatis in the genital tract. Circulating antibodies to the chlamydial 60kDa heat shock protein (hsp60) is a specific indicator of tubal occlusion and, furthermore, correlates with the continued presence of this micro-organism in the genital tract of non-human primates. Screening for both cervical IgA antibodies to C. trachomatis and serum IgG anti-chlamydial hsp60 appears to provide the best indication as to which women may be harbouring C. trachomatis.