Pathogenesis of Fallopian tube damage caused by Chlamydia trachomatis infections

Chlamydia trachomatis is the leading cause of bacterial sexually transmitted disease worldwide resulting in 4–5 million new cases of Chlamydia annually and an estimated 100 million cases per annum. Infections of the lower female genital tract (FGT) frequently are asymptomatic so they often remain undiagnosed or untreated. If infections are either not resolved, or are left untreated, chlamydia can ascend to the upper FGT and infect the fallopian tubes (FTs) causing salpingitis that may lead to functional damage of the FTs and tubal factor infertility (TFI). Clinical observations and experimental data have indicated a role for antibodies against C. trachomatis proteins such as the 60 kDa heat-shock protein 60 (cHSP60) in the immunopathogenesis of TFI. When released from infected cells cHSP60 can induce pro-inflammatory immune responses that may functionally impair the FTs leading to fibrosis and luminal occlusion. Chlamydial pathogenesis of irreversible and permanent tubal damage is a consequence of innate and adaptive host immune responses to ongoing or repeated infections. The extracellular matrix (ECM) that is regulated by metalloproteinases (MMPs) may also be modified by chlamydial infections of the FGT. This review will highlight protective and pathogenic immune responses to ongoing and repeated chlamydial infections of the FGT. It will also present two recent hypotheses to explain mechanisms that may contribute to FT damage during a C. trachomatis infection. If Chlamydia immunopathology can be controlled it might yield a method of inducing fibrosis and thus provide a means of non-surgical permanent contraception for women.

Evaluation of intra- and extra-epithelial secretory IgA in chlamydial infections

IgA is an important mucosal antibody that can neutralize mucosal pathogens by either preventing attachment to epithelia (immune exclusion) or alternatively inhibit intraepithelial replication following transcytosis by the polymeric immunoglobulin receptor (pIgR). Chlamydia trachomatis is a major human pathogen that initially targets the endocervical or urethral epithelium in women and men, respectively. As both tissues contain abundant SIgA we assessed the protection afforded by IgA targeting different chlamydial antigens expressed during the extra and intraepithelial stages of infection. We developed an in vitro model utilizing polarizing cells expressing the murine pIgR together with antigen-specific mouse IgA, and an in vivo model utilizing pIgR-/- mice. SIgA targeting the extraepithelial chlamydial antigen, the major outer membrane protein (MOMP), significantly reduced infection in vitro by 24 % and in vivo by 44 %. Conversely, pIgR-mediated delivery of IgA targeting the intraepithelial inclusion membrane protein A (IncA) bound to the inclusion but did not reduce infection in vitro or in vivo. Similarly, intraepithelial IgA targeting the secreted protease Chlamydia protease-like activity factor (CPAF) also failed to reduce infection. Together, these data suggest the importance of pIgR-mediated delivery of IgA targeting extra but not intraepithelial chlamydial antigens for protection against a genital tract infection.

Geographic Variation of Notified Ross River Virus Infections in Queensland, Australia, 1985-1996

The spatial and temporal variations of Ross River virus infections reported in Queensland, Australia, between 1985 and 1996 were studied by using the Geographic Information System. The notified cases of Ross River virus infection came from 489 localities between 1985 and 1988, 805 between 1989 and 1992, and 1,157 between 1993 and 1996 (chi2(df = 2) = 680.9; P < 0.001). There was a marked increase in the number of localities where the cases were reported by 65 percent for the period of 1989-1992 and 137 percent for 1993-1996, compared with that for 1985-1988. The geographic distribution of the notified Ross River virus cases has expanded in Queensland over recent years. As Ross River virus disease has impacted considerably on tourism and industry, as well as on residents of affected areas, more research is required to explore the causes of the geographic expansion of the notified Ross River virus infections.

Economic evaluation and catheter-related bloodstream infections

Catheter-related bloodstream infections are a serious problem. Many interventions reduce risk, and some have been evaluated in cost-effectiveness studies. We review the usefulness and quality of these economic studies. Evidence is incomplete, and data required to inform a coherent policy are missing. The cost-effectiveness studies are characterized by a lack of transparency, short time-horizons, and narrow economic perspectives. Data quality is low for some important model parameters. Authors of future economic evaluations should aim to model the complete policy and not just single interventions. They should be rigorous in developing the structure of the economic model, include all relevant economic outcomes, use a systematic approach for selecting data sources for model parameters, and propagate the effect of uncertainty in model parameters on conclusions. This will inform future data collection and improve our understanding of the economics of preventing these infections.

Chlamydial infection and spatial ascension of the female genital tract : a novel hybrid cellular automata and continuum mathematical model

Sexually transmitted chlamydial infection initially establishes in the endocervix in females, but if the infection ascends the genital tract, significant disease, including infertility, can result. Many of the mechanisms associated with chlamydial infection kinetics and disease ascension are unknown. We attempt to elucidate some of these processes by developing a novel mathematical model, using a cellular automata–partial differential equation model. We matched our model outputs to experimental data of chlamydial infection of the guinea-pig cervix and carried out sensitivity analyses to determine the relative influence of model parameters. We found that the rate of recruitment and action of innate immune cells to clear extracellular chlamydial particles and the rate of passive movement of chlamydial particles are the dominant factors in determining the early course of infection, magnitude of the peak chlamydial time course and the time of the peak. The rate of passive movement was found to be the most important factor in determining whether infection would ascend to the upper genital tract. This study highlights the importance of early innate immunity in the control of chlamydial infection and the significance of motility-diffusive properties and the adaptive immune response in the magnitude of infection and in its ascension.

Effect of female sex hormones on Chlamydia trachomatis growth and gene expression

Transmissible diseases are re-emerging as a global problem, with Sexually Transmitted Diseases (STDs) becoming endemic. Chlamydia trachomatis is the leading cause of bacterially-acquired STD worldwide, with the Australian cost of infection estimated at $90 - $160 million annually. Studies using animal models of genital tract Chlamydia infection suggested that the hormonal status of the genital tract epithelium at the time of exposure may influence the outcome of infection. Oral contraceptive use also increased the risk of contracting chlamydial infections compared to women not using contraception. Generally it was suggested that the outcome of chlamydial infection is determined in part by the hormonal status of the epithelium at the time of exposure. Using the human endolmetrial cell line ECC-1 this study investigated the effects of C. trachomatis serovar D infection, in conjunction with the female sex hormones, 17β-estradiol and progesterone, on chlamydial gene expression. While previous studies have examined the host response, this is the first study to examine C.trachomatis gene expression under different hormonal conditions. We have highlighted a basic model of C. trachomatis gene regulation in the presence of steroid hormones by identifying 60 genes that were regulated by addition of estradiol and/or progesterone. In addition, the third chapter of this thesis discussed and compared the significance of the current findings in the context of data from other research groups to improve our understanding of the molecular basis of chlamydial persistence under hormonal different conditions. In addition, this study analysed the effects of these female sex hormones and C. trachomatis Serovar D infection, on host susceptibility and bacterial growth. Our results clearly demonstrated that addition of steroid hormones not only had a great impact on the level of infectivity of epithelial cells with C.trachomatis serovar D, but also the morphology of chlamydial inclusions was affected by hormone supplementation.

Effects of inoculating dose on the kinetics of Chlamydia muridarum genital infection in female mice

Chlamydia trachomatis infections have been implicated in problems such as pelvic inflammatory disease and infertility in females. Although there are some studies examining the kinetics of ascending infection, there is limited information on the kinetics of pathology development and cellular infiltrate into the reproductive tissues in relation to the effects of inoculating dose, and a better understanding of these is needed. The murine model of female genital tract Chlamydia muridarum infection is frequently used as a model of human C. trachomatis reproductive tract infection. To investigate the kinetics of ascending genital infection and associated pathology development, female BALB/c mice were intravaginally infected with C. muridarum at doses ranging from 5102 to 2.6106 inclusion forming units. We found that the inoculating dose affects the course of infection and the ascension of bacteria, with the highest dose ascending rapidly to the oviducts. By comparison, the lowest dose resulted in the greatest bacterial load in the lower reproductive tract. Interestingly, we found that the dose did not significantly affect inflammatory cell infiltrate in the various regions. Overall, this data show the effects of infectious dose on the kinetics of ascending chlamydial infection and associated inflammatory infiltration in BALB/c mice.

Persistent chlamydial infections : role in inflammation and challenges for vaccine development.

The development of chlamydial vaccines continues to be a major challenge for researchers. While acute infections are the main target of vaccine development groups, Chlamydia is well known for its ability to establish chronic or persistent infections in its host. To date, little effort has focussed specifically on the challenges of vaccines to successfully combat the chronic or persistent phase of the disease and yet this will be a necessary aspect of any fully successful chlamydial vaccine. This short review specifically examines the phenomenon of chlamydial persistence and the unique challenges that this brings to vaccine development.