Catherine O’Connell Ph.D.

EMAIL: catherine.oconnell@unc.edu

PERSONAL WEBSITE: https://www.med.unc.edu/childrensresearch/directory/catherine-oconnell-phd/

PUBLICATIONS: Publications Link

Natural immunity to chlamydial genital tract infection in women
Pelvic inflammatory disease (PID) continues to pose great risk to the reproductive health of women worldwide. Its potentially devastating long-term sequelae can persist throughout a woman’s reproductive years. PID occurs when sexually transmitted infections ascend from the cervix to the uterus and oviducts, resulting in endometritis and salpingitis. Infection with C. trachomatis, Neisseria gonorrhoeae, or both, may lead to PID and associated morbidities including infertility, ectopic pregnancy, and chronic pelvic pain. Currently, it is impossible to predict an individual’s risk for developing disease with infection so biomarkers that identify women at elevated risk for reproductive morbidities are needed. In collaboration with Xiaojing Zheng, Toni Darville and many others I have participated in human studies of chlamydial genital tract infections in women with the goal of increasing understanding of pathogenesis and the evolution of natural immunity. Transcriptional profiling that compared systemic responses of women with chlamydial PID to women with local cervical infection, identified specific, disease-associated inflammatory pathways and revealed how gonorrheal co-infection depressed developing cell-mediated immunity. We also defined a blood-borne, 21 gene biomarker panel that diagnoses endometritis in asymptomatically infected women with high chlamydial burden. However, this study revealed issues associated with sensitivity of systemic biomarkers and we have recently investigated the feasibility of profiling responses at active infection sites. We have also been able to identify specific chlamydial antigens recognized by CD4+ and CD8+ T cells associated with protective immunity among a high-risk cohort of women. Most recently, I have begun to explore the potential to extend profiling technologies to investigation of the transcriptional responses of STI pathogens and the cervicovaginal microbiome.

Role of the chlamydial plasmid in virulence.
Relatively little is understood regarding the pathogenic mechanisms by which C. trachomatis directly causes disease although it has been clear that host-pathogen interactions leading damaging immune pathology are central to this process. I developed a method to cure the resident plasmid from C. muridarum and C. trachomatis and, in collaboration with Toni Darville, demonstrated that the resultant plasmid-cured derivatives were significantly attenuated in their ability to cause genital tract disease in the murine model. These discoveries revealed the central role of the chlamydial plasmid in virulence and the potential to derive attenuated chlamydial strains that serve as vaccine candidates. Loss of the chlamydial plasmid is pleiotropic. In addition to reduced pro-inflammatory signaling, we also observed reduced infectivity in vitro. We were subsequently able to demonstrate that the infectivity defect reduced the competitiveness of plasmid-cured derivatives during infection and that this likely serves as the primary selective mechanism for plasmid retention. We also observed down-regulation of conserved chromosomal loci including genes involved in glycogen biosynthesis. Furthermore, restricting the availability of glucose to replicating chlamydiae impaired glycogen accumulation and reduced their ability to elicit TLR2-activation, demonstrating that C. trachomatis modulates virulence gene expression in response to environmental signals.