Kelly A. Cunningham

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 5 × 102 to 2.6 × 106 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.

Microbial colonization of follicular fluid: alterations in cytokine expression and adverse assisted reproduction technology outcomes

BACKGROUND Previous studies have measured cytokines expressed within follicular fluid and compared the profiles with the aetiology of infertility and/or successful or unsuccessful assisted reproduction technology (ART) outcomes. METHODS In this study, 71 paired follicular fluid and vaginal secretions collected from ART patients were cultured to detect microorganisms and tested for the presence of cytokines. Patient specimens were selected for assay based on two criteria: whether the follicular fluid specimen was colonized (with microorganisms prior to oocyte retrieval) or contaminated by vaginal flora and; the aetiology of infertility. Patients included fertile women (with infertile male partners; n = 18), women with endometriosis (n = 16) or polycystic ovary syndrome (PCOS, n = 14), or couples with a history of genital tract infection (n = 9) or idiopathic infertility (n = 14). RESULTS Microorganisms and cytokines were detected within all tested specimens. Colonizing microorganisms in follicular fluid were associated with: decreased fertilization rates for fertile women (P = 0.005), women with endometriosis (P = 0.0002) or PCOS (P = 0.002) compared with women whose follicular fluid was contaminated at the time of oocyte retrieval and with decreased pregnancy rates for couples with idiopathic infertility (P = 0.001). A single cytokine was discriminatory for women with an idiopathic aetiology of infertility (follicular fluid interleukin (IL)-18). Unique cytokine profiles were also associated with successful fertilization (IL-1α, IL-1β, IL-18 and vascular endothelial growth factor). CONCLUSIONS Follicular fluid is not sterile. Microorganisms colonizing follicular fluid and the ensuing cytokine response could be a further as yet unrecognized cause and/or predictor of adverse ART outcomes and infertility.

Poly-Immunoglobulin receptor-mediated transport of IgA into the male genital tract is important for clearance of chlamydia muridarum infection

Problem  Chlamydia trachomatis is the most common sexually transmitted infection worldwide. While infection in females requires a Th1 response for clearance, such a response in males may disrupt the immune privileged nature of the male reproductive tract, potentially contributing to infertility.

Chlamydia muridarum major-outer membrane protein-specific antibodies inhibit in vitro infection but enhance pathology in vivo

Citation Cunningham KA, Carey AJ, Hafner L, Timms P, Beagley KW. Chlamydia muridarum major outer membrane protein‐specific antibodies inhibit in vitro infection but enhance pathology in vivo. Am J Reprod Immunol 2011; 65: 118–126

Progesterone activates multiple innate immune pathways in Chlamydia trachomatis-infected endocervical cells.

Susceptibility to Chlamydia trachomatis infection is increased by oral contraceptives and modulated by sex hormones. We therefore sought to determine the effects of female sex hormones on the innate immune response to C. trachomatis infection.

Proof of concept: A bioinformatic and serological screening method for identifying new peptide antigens for Chlamydia trachomatis related sequelae in women.

This study aimed to identify new peptide antigens from Chlamydia (C.) trachomatis in a proof of concept approach which could be used to develop an epitope-based serological diagnostic for C. trachomatis related infertility in women. A bioinformatics analysis was conducted examining several immunodominant proteins from C. trachomatis to identify predicted immunoglobulin epitopes unique to C. trachomatis. A peptide array of these epitopes was screened against participant sera. The participants (all female) were categorized into the following cohorts based on their infection and gynecological history; acute (single treated infection with C. trachomatis), multiple (more than one C. trachomatis infection, all treated), sequelae (PID or tubal infertility with a history of C. trachomatis infection), and infertile (no history of C. trachomatis infection and no detected tubal damage). The bioinformatics strategy identified several promising epitopes. Participants who reacted positively in the peptide 11 ELISA were found to have an increased likelihood of being in the sequelae cohort compared to the infertile cohort with an odds ratio of 16.3 (95% c.i. 1.65-160), with 95% specificity and 46% sensitivity (0.19-0.74). The peptide 11 ELISA has the potential to be further developed as a screening tool for use during the early IVF work up and provides proof of concept that there may be further peptide antigens which could be identified using bioinformatics and screening approaches.

A comparison of the effects of a chlamydial vaccine administered during or after a C. muridarum urogenital infection of female mice.

Research into an efficacious Chlamydia trachomatis vaccine is ongoing, however, there has been no examination into the timing of vaccine administration to either asymptomatically or previously infected individuals. Using the female Chlamydia muridarum genital tract mouse model, we examined this aspect of vaccine development. Our results show timing of vaccination affected the production of systemic antibodies, but had minimal effects on mucosal antibody production. Vaccination during an active infection or after a resolved infection did not provide protection against re-exposure to Chlamydia, and did not exacerbate the development of pathological sequelae in infected mice. This demonstrates that vaccination may not be protective in individuals who are seropositive for an acute or previous chlamydial infection.

Characterization of In Vitro Chlamydia muridarum Persistence and Utilization in an In Vivo Mouse Model of Chlamydia Vaccine

Chlamydia trachomatis genital tract infections are easily treated with antibiotics; however, the majority of infections are asymptomatic and therefore untreated, highlighting the need for a vaccine. Because most infections are asymptomatic, vaccination could potentially be administered to individuals who may have an acute infection at that time. In such individuals, the effect of vaccination on the existing infection is unknown; however, one potential outcome could be the development of a persistent infection. In vitro chlamydial persistence has been well characterized in various strains; however, there have been no reported studies in C. muridarum.

ORIGINAL ARTICLE: Poly-Immunoglobulin Receptor-Mediated Transport of IgA into the Male Genital Tract is Important for Clearance of Chlamydia muridarum Infection: IGA IN CLEARANCE OF MALE CHLAMYDIAL INFECTION

Problem  Chlamydia trachomatis is the most common sexually transmitted infection worldwide. While infection in females requires a Th1 response for clearance, such a response in males may disrupt the immune privileged nature of the male reproductive tract, potentially contributing to infertility.

ORIGINAL ARTICLE: Poly-Immunoglobulin Receptor-Mediated Transport of IgA into the Male Genital Tract is Important for Clearance of Chlamydia muridarum Infection

Problem  Chlamydia trachomatis is the most common sexually transmitted infection worldwide. While infection in females requires a Th1 response for clearance, such a response in males may disrupt the immune privileged nature of the male reproductive tract, potentially contributing to infertility.