Action Needed on Chlamydia Vaccines.

Chlamydia trachomatis is the most common infectious disease in the USA for which the Centers for Disease Control (CDC) collects case reports. Its prevalence in young women is a public health crisis given the threat to their reproductive health. Consequently, development of a vaccine to prevent infection should be prioritized.

Evaluation of the utility of a rapid test for syphilis at a sexually transmitted disease clinic in Buenos Aires, Argentina.

Even though syphilis can be easily diagnosed by simple and low-cost laboratory methods, it continues to be an important health problem. Rapid tests (RT) for the detection of treponemal antibodies can facilitate earlier diagnosis, access to treatment and linkage to care. The aim of this study was to analyse the usefulness of the incorporation of a RT in the detection of patients infected with T. pallidum in a sexually-transmitted disease (STD) clinic. Between March and December 2015, a syphilis RT was offered to patients who spontaneously attended the clinic. Conventional serology testing was additionally indicated to every participant. The RT for syphilis was offered to 1887 patients, of whom 31.1% agreed to get tested. VDRL test was performed in 84.0% of patients that were also tested with syphilis RT, with a significantly higher frequency observed among participants with reactive RT (94.3% vs. 79.8%, p < 0.001). These results showed that 33.7% of the participants were reactive for the RT and 27.0% were reactive for the VDRL test. Both tests were reactive in 24.9% and non-reactive in 64.3%. A high prevalence of active syphilis was detected in patients attending the clinic. The use of a syphilis RT had a positive impact, which in combination with the VDRL test increased the number of patients that were effectively diagnosed.

The Unique Microbiology and Molecular Pathogenesis of Mycoplasma genitalium.

Mycoplasma genitalium is increasingly appreciated as a common cause of sexually transmitted disease syndromes, including urethritis in men and cervicitis, endometritis, pelvic inflammatory disease, and possibly preterm birth, tubal factor infertility, and ectopic pregnancy in women. Despite these disease associations, which parallel those of Chlamydia trachomatis and Neisseria gonorrhoeae, the mechanisms by which this pathogen elicits inflammation, causes cellular damage, and persists in its only natural host (humans) are unique and are not fully understood. The purpose of this review is to briefly provide a historical background on the discovery, microbiology, and recognition of M. genitalium as a pathogen, and then summarize the recent advances in our understanding of the molecular biology and pathogenesis of this unique urogenital organism. Collectively, the basic scientific discussions herein should provide a framework for understanding the clinical and epidemiological outcomes described in the accompanying articles in this supplemental issue.

Injectable Progestin-Only Contraception is Associated With Increased Levels of Pro-Inflammatory Cytokines in the Female Genital Tract.

PROBLEM: Genital inflammatory changes may be a mechanism of increased HIV risk among injectable progestin-only contraception (IPC) users. METHOD OF STUDY: We conducted a cross-sectional analysis of 376 Kenyan and South African women. Genital cytokines and secretory leukocyte peptidase inhibitor concentrations in a reference population were compared to IPC users and women with reproductive tract infections. RESULTS: No significant variability in marker concentrations was observed by age or site. Depot medroxyprogesterone acetate (DMPA) users had significantly higher MIP-1α, MIP-1ß, IL-6, IL-8, IP-10, and RANTES concentrations. Norethisterone oenanthate users had significantly higher IL-6, IL-8, and RANTES concentrations. Women with sexually transmitted infections had variable inflammation, and women with bacterial vaginosis exhibited a mixed profile of up and downregulation. CONCLUSION: The finding of substantial mucosal inflammation among DMPA users provides evidence which, combined with the results of prior studies, suggests that DMPA may create an immune environment conducive to HIV target cell recruitment and inhibitory for antiviral activity.

Immunity, immunopathology, and human vaccine development against sexually transmitted Chlamydia trachomatis.

This review examines the immunity, immunopathology, and contemporary problems of vaccine development against sexually transmitted Chlamydia trachomatis. Despite improved surveillance and treatment initiatives, the incidence of C. trachomatis infection has increased dramatically over the past 30 years in both the developed and developing world. Studies in animal models have shown that protective immunity to C. trachomatis is largely mediated by Th1 T cells producing IFN-γ which is needed to prevent dissemination of infection. Similar protection appears to develop in humans but in contrast to mice, immunity in humans may take years to develop. Animal studies and evidence from human infection indicate that immunity to C. trachomatis is accompanied by significant pathology in the upper genital tract. Although no credible evidence is currently available to indicate that autoimmunity plays a role, nevertheless, this underscores the necessity to design vaccines strictly based on chlamydial-specific antigens and to avoid those displaying even minimal sequence homologies with host molecules. Current advances in C. trachomatis vaccine development as well as alternatives for designing new vaccines for this disease are discussed. A novel approach for chlamydia vaccine development, based on targeting endogenous dendritic cells, is described.

Mycoplasma genitalium infection activates cellular host defense and inflammation pathways in a 3-dimensional human endocervical epithelial cell model.

BACKGROUND: Because Mycoplasma genitalium is a prevalent and emerging cause of sexually transmitted infections, understanding the mechanisms by which M. genitalium elicits mucosal inflammation is an essential component to managing lower and upper reproductive tract disease syndromes in women. METHODS: We used a rotating wall vessel bioreactor system to create 3-dimensional (3-D) epithelial cell aggregates to model and assess endocervical infection by M. genitalium. RESULTS: Attachment of M. genitalium to the host cell's apical surface was observed directly and confirmed using immunoelectron microscopy. Bacterial replication was observed from 0 to 72 hours after inoculation, during which time host cells underwent ultrastructural changes, including reduction of microvilli, and marked increases in secretory vesicle formation. Using genome-wide transcriptional profiling, we identified a host defense and inflammation signature activated by M. genitalium during acute infection (48 hours after inoculation) that included cytokine and chemokine activity and secretion of factors for antimicrobial defense. Multiplex bead-based protein assays confirmed secretion of proinflammatory cytokines, several of which are involved in leukocyte recruitment and hypothesized to enhance susceptibility to human immunodeficiency type 1 infection. CONCLUSIONS: These findings provide insight into key molecules and pathways involved in innate recognition of M. genitalium and the response to acute infection in the human endocervix.

Virus del papiloma e indicaciones de la vacuna tetravalente / Papillomavirus and indications of tetravalent

El virus del papiloma humano es una de las infecciones de transmisión sexual más comunes, se encuentra asociado con varias enfermedades desde cáncer cervical y anal, hasta verrugas genitales. Sus particulares inmunológicas le permiten subsistir en algunos pacientes y causar enfermedades malignas. Con la aprobación de la vacuna tetravalente contra el VPH los médicos poseemos una nueva arma en la prevención primaria contra el cáncer cervical, las verrugas genitales y el cáncer anal. Este trabajo revisa los conocimientos actuales sobre esta vacuna y sus indicaciones en medicina general.

[Efficacy of azithromycin and its impact on cytokine system in urogenital infections].

Seventy five patients with urogenital chlamydial and mycoplasmic infections were enrolled in the trial. In the etiotropic therapy azithromycin was used in the standard dosage (1.0-1.5 g) depending on the infection. The treatment with azithromycin, in addition to the high eradication rates, was also evident of its effect on the cytokine levels in the patients, that was characteristic of a significant increase of the IFN-gamma level and a decrease of the IL-1beta and IL-6 levels in the blood.

Transmission probabilities and durations of immunity for three pathogenic group B Streptococcus serotypes.

Group B Streptococcus (GBS) remains a major cause of neonatal sepsis and is an emerging cause of invasive bacterial infections. The 9 known serotypes vary in virulence, and there is little cross-immunity. Key parameters for planning an effective vaccination strategy, such as average length of immunity and transmission probabilities by serotype, are unknown. We simulated GBS spread in a population using a computational model with parameters derived from studies of GBS sexual transmission in a college dormitory. Here we provide estimates of the duration of immunity relative to the transmission probabilities for the 3 GBS serotypes most associated with invasive disease: Ia, III, and V. We also place upper limits on the durations of immunity for serotype Ia (570 days), III (1125 days) and V (260 days). Better transmission estimates are required to establish the epidemiological parameters of GBS infection and determine the best vaccination strategies to prevent GBS disease.

Diagnosis and follow-up of genital chlamydial infection by direct methods and by detection of serum IgG, IgA and secretory IgA.

PURPOSE: To determine the prevalence of Chlamydia trachomatis infection in a high-risk population by direct and indirect methods and to evaluate the diagnosis of secretory immunoglobulin A (sIgA). PATIENTS AND METHODS: Urethral or endocervical specimens from 78 patients (48 females and 30 males) were examined by cell culture, direct fluorescence assay, PCR Cobas Amplicor (Roche Molecular Diagnostics), and sIgA was detected by the recombinant lipopolysaccharide (LPS)-enzyme-linked immunoassay (rELISA). Serum from each patient was also obtained and analysed for the presence of IgG and IgA antibody by in-house microimmunofluorescence (MIF) and by the rELISA method (Medac, Hamburg, Germany). RESULTS: The overall C. trachomatis prevalence determined by direct methods was 28%. The detection of sIgA antibodies was significantly higher in the group of patients with a positive direct detection (50%) than in the group of negative direct detection (10.7%). The Chlamydia-specific IgA antibodies were detected by the rELISA in 40.9 and 53.6% of group I (positive direct detection) and group II patients (negative direct detection), respectively. The species-specific IgA antibodies were detected by the MIF method in 18.2 and 16.1% of group I and II patients, respectively. Chlamydia genus-specific IgG antibodies were detected by the rELISA in 86.4 and 83.9% of group I and group II patients and, C. trachomatis specific IgG were present in 81.8 and 73.2% of group I and group II patients, respectively, as assessed by the MIF test. CONCLUSION: Combining the positive direct methods and/or positive sIgA antibody results from cervical or urethral specimens had an indication of current C. trachomatis infection.

HtrA, RseP, and Tsp proteins do not elicit a pathology-related serum IgG response during sexually transmitted infection with Chlamydia trachomatis.

Chlamydia trachomatis sexually transmitted infection can cause serious reproductive morbidities. This study determined the prevalence of a serum IgG response to C. trachomatis putative stress response proteins in women, to test for an association with genital tract pathology. There was no significant association of serum IgG reactive with C. trachomatis HtrA, Tsp, or RseP with infection or pathology. cHSP60 serum IgG prevalence was significantly associated with infection compared to IgG negative infertile controls, but not with upper genital tract pathology. Serum IgG(1-4) antibody subclasses reactive with these antigens was not significantly different between cohorts, although different responses to each antigen were detected.

The mucosal immune response to Chlamydia trachomatis infection of the reproductive tract in women.

Sexually transmitted Chlamydia trachomatis infection is an important public health concern with major adverse effects on female reproductive tract health and function. The magnitude of reproductive morbidity associated with sexually transmitted C. trachomatis infection is enormous, however to date no prophylactic vaccine is available. In part this is due to the lack of information on the mucosal immunobiology of the host-pathogen interaction and correlates of protective immunity during genital C. trachomatis infection. In this review, we focus on current knowledge of mucosal innate and adaptive immune responses in the female genital tract during C. trachomatis infection, which will eventually help in the development of a vaccine for prevention of chlamydial infection.

Chlamydial protease-like activity factor--insights into immunity and vaccine development.

Chlamydia trachomatis is a Gram-negative obligate intracellular pathogen that remains the leading cause of bacterial sexually transmitted disease worldwide, despite the availability of efficacious antimicrobial therapy. Given that chlamydial infections cause severe pathological sequelae in the upper genital tract, a licensed vaccine to prevent infection and disease would be an ideal solution. Chlamydial protease-like activity factor (CPAF) is a protein secreted in considerable amounts into the cytosol of infected cells and released into the extracellular milieu upon cellular lysis, which therefore is accessible to the host immune system. This is further substantiated by the observation that CPAF is immunodominant among other antigens in Chlamydia sero-positive humans. The efficacy of vaccination with CPAF against genital chlamydial challenge has been evaluated extensively in the murine model. This review will discuss important insights into the potential of CPAF as a component of an anti-chlamydial vaccine.

Impact of T. vaginalis infection on innate immune responses and reproductive outcome.

Trichomonas vaginalis is the most common non-viral sexually transmitted pathogen. The infection is prevalent in reproductive age women and is associated with vaginitis, endometritis, adnexitis, pyosalpinx, infertility, preterm birth, low birth weight, bacterial vaginosis, and increased risk of cervical cancer, HPV, and HIV infection. In men, its complications include urethritis, prostatitis, epididymitis, and infertility through inflammatory damage or interference with the sperm function. The infection is often asymptomatic and recurrent despite the presence of specific antibodies, suggesting the importance of the innate immune defense. T. vaginalis adhesion proteins, cysteine proteases, and the major parasite lipophosphoglycan (LPG) play distinct roles in the pathogenesis and evasion of host immunity. LPG plays a key role in the parasite adherence and signaling to human vaginal and cervical epithelial cells, which is at least in part mediated by galectins. The epithelial cells respond to T. vaginalis infection and purified LPG by selective upregulation of proinflammatory mediators. At the same time, T. vaginalis triggers an immunosuppressive response in monocytes, macrophages, and dendritic cells. The molecular mechanisms underlying reproductive complications and epidemiologic risks associated with T. vaginalis infection remain to be elucidated.

Modeling the impact of potential vaccines on epidemics of sexually transmitted Chlamydia trachomatis infection.

BACKGROUND: We investigated the likely impact of vaccines on the prevalence of and morbidity due to Chlamydia trachomatis (chlamydia) infections in heterosexual populations. METHODS: An individual-based mathematical model of chlamydia transmission was developed and linked to the infection course in chlamydia-infected individuals. The model describes the impact of a vaccine through its effect on the chlamydial load required to infect susceptible individuals (the "critical load"), the load in infected individuals, and their subsequent infectiousness. The model was calibrated using behavioral, biological, and clinical data. RESULTS: A fully protective chlamydia vaccine administered before sexual debut can theoretically eliminate chlamydia epidemics within 20 years. Partially effective vaccines can still greatly reduce the incidence of chlamydia infection. Vaccines should aim primarily to increase the critical load in susceptible individuals and secondarily to decrease the peak load and/or the duration of infection in vaccinated individuals who become infected. Vaccinating both sexes has a beneficial impact on chlamydia-related morbidity, but targeting women is more effective than targeting men. CONCLUSIONS: Our findings can be used in laboratory settings to evaluate vaccine candidates in animal models, by regulatory bodies in the promotion of candidates for clinical trials, and by public health authorities in deciding on optimal intervention strategies.

Levels of innate immune factors in genital fluids: association of alpha defensins and LL-37 with genital infections and increased HIV acquisition.

BACKGROUND: Several mucosal innate immune proteins exhibit HIV inhibitory activity and their analogues are potential microbicide candidates. However, their clinical associations and in-vivo role in cervicovaginal host defense against HIV acquisition are poorly defined. METHODS: Cervicovaginal secretions (CVSs) were collected from HIV uninfected Kenyan sex workers at enrolment into an HIV prevention trial. After trial completion, CVS from participants acquiring HIV (cases) and matched controls were assessed for levels of innate immune factors and HIV neutralizing capacity, by blinded investigators. Cross-sectional and prospective associations of innate immune factors were examined. RESULTS: CVS contained high levels of defensins (human neutrophil peptide-1-3 and human beta defensin-2-3), LL-37 and secretory leukocyte protease inhibitor. Regulated upon activation normal T-cell expressed and secreted levels were lower, and IFNalpha was undetectable. CVS from 20% of participants neutralized a clade A primary HIV isolate, and 12% neutralized both clade A and C isolates. HIV neutralization was correlated with human neutrophil peptide-1-3 (alpha-defensins) and LL-37 levels. However, alpha-defensin and LL-37 levels were increased in participants with bacterial sexually transmitted infections and were independently associated with increased HIV acquisition in multivariate analysis. CONCLUSIONS: Despite significant HIV inhibitory activity, cervicovaginal levels of alpha-defensins and LL-37 were associated with increased HIV acquisition, perhaps due to their association with bacterial sexually transmitted infections.

Sexually transmitted diseases in the USA: temporal trends.

This paper reviews the temporal trends in sexually transmitted diseases (STDs) and discusses the factors affecting the epidemiology of bacterial STDs.

Innate immunity at the mucosal surface: role of toll-like receptor 3 and toll-like receptor 9 in cervical epithelial cell responses to microbial pathogens.

Toll-like receptors (TLRs) are a family of pattern recognition receptors that recognize distinct molecular patterns shared by a broad range of pathogens, including nucleic acids. TLR9, for example, recognizes unmethylated deoxycytidyl-phosphate-deoxyguanosine (CpG) dinucleotides that are common in bacterial and some viral nucleic acids, whereas TLR3 recognizes double-stranded RNA and TLR7/TLR8 recognize single-stranded RNA, which would be found during viral replication. We were interested in whether TLR3, TLR9, and the related TLR9 family members TLR7/TLR8 might play a role in antiviral immune defense at the mucosal epithelial surface of the lower female reproductive tract. We studied cervical epithelial cells and found that they expressed mRNA for TLR3, TLR9, and TLR7, but had only a weak signal for TLR8. For TLR3 and TLR9, protein expression was confirmed to be intracellular. When epithelial cells were incubated with polyinosine-polycytidylic acid and CpG oligodinucleotides, we observed dose-dependent upregulation of interleukin-8 secretion. However, cells failed to respond to a variety of TLR7/TLR8 ligands. Polyinosine-polycytidylic acid also induced production of interferon-beta and chemokine C-C motif ligand 5, whereas CpG DNA did not. Cell activation by synthetic oligodinucleotides occurred only in response to the B class sequences, and required the presence of human-specific CpG motifs. In addition, responses to CpG oligodinucleotides could be inhibited by chloroquine, demonstrating the requirement for endosomal maturation. These data demonstrate that mucosal epithelial cells express functional TLR3 and TLR9, and suggest that these receptors play a role in regulating the proinflammatory cytokine and antiviral environment of the lower female reproductive tract during infection with viral and bacterial pathogens.

Immunology of the human genital tract.

PURPOSE OF REVIEW: Despite much interest in the mechanisms of immune protection against sexually transmitted diseases (STDs), little is known about the role of the immune system in the genital tract. A better knowledge is needed to understand not only host protection against STDs, but also how tolerance is established in pregnancy to avoid rejection of the foetus. RECENT FINDINGS: The immune system of the genital tract displays characteristic features that are unique, and therefore distinct from those of other mucosal and systemic immune sites. It is functionally separate from the mucosal immune systems of the lung or intestine, and contrary to these systems, antibodies in the genital tract are dominated by IgG and not IgA. Most of the IgA is polymeric and consists of equal proportions IgA1 and IgA2. Polymeric IgA is actively transported via the polymeric immunoglobulin receptor on the basolateral surface of the epithelial cell, whereas it is not known how IgG antibodies are secreted. Antibody levels and isotypes exhibit strong hormonal dependence. Less is known about cell-mediated immune responses in the genital tract. Interest has focused on adhesion molecules, the existence of regulatory T and natural killer cells, and whether innate and early adaptive immune responses may be stimulated by local vaginal, intranasal or intestinal vaccinations. These topics are reviewed here and the most recent developments in these areas are reported. SUMMARY: A greater knowledge of immune activation and the homing of leukocytes to the genital tract is important for future attempts to design vaccines against STDs, as well as in understanding foetal tolerance.

Recognition of the 60 kilodalton cysteine-rich outer membrane protein OMP2 by CD4(+) T cells from humans infected with Chlamydia trachomatis.

T cell-mediated immunity is important in the control of chlamydia infection but chlamydia-specific T cells are also implicated in the inflammation and tissue damage which characterize chlamydia associated diseases. To investigate target antigens of the T cell-mediated immune response to chlamydia infection, Chlamydia trachomatis-specific CD4+ T cell clones were isolated from a patient with chlamydia-induced reactive arthritis. T cell immunoblotting indicated that an antigen of approximately 60 kilodaltons molecular mass was recognized, and recombinant 60 kilodalton cysteine-rich outer membrane 2 (OMP2) proved to be stimulatory. By using deletion constructs and synthetic peptides an epitope presented by HLA-DRB1*0401 was defined and proved to contain the nonamer peptide within the OMP2 sequence predicted to have the greatest binding affinity for DRB1*0401 The sequence of the epitope is conserved in all C. trachomatis strains but not in C. pneumoniae. Investigation of patients with acute urethritis and additional patients with sexually acquired reactive arthritis showed that OMP2-reactive T cells were readily detectable in peripheral blood and synovial fluid. Thus OMP2 is a target antigen of the T cell-mediated immune response to CT infection.