- Determination of innate immune receptors and signaling pathways stimulated by chlamydiae, and their role in generating a protective vs. pathogenic immune response. In vitro and murine model studies are being used to determine signaling pathways and adaptor proteins important in the pathogenesis of genital tract disease due to Chlamydia trachomatis.
Dr. Darville’s research team is successfully using plasmid-deficient attenuated chlamydial strains that do not induce pathology but lead to induction of protective adaptive immune responses, as tools for separating pathogen-specific virulence factors from pathogen-host interactions that drive protection.
Related studies include examination of the potential that vaccination of female rhesus macaques with attenuated plasmid-deficient human strains of C. trachomatis will protect them from developing disease after infection with wild-type, fully virulent organisms. This work will have direct implications for considering attenuated plasmid-deficient C. trachomatis strains as potential vaccine candidates for humans.
- Adaptive T cell responses to chlamydial infection. Dr. Darville’s laboratory is actively involved in determining chlamydial proteins that induce protective CD4+ Th1 responses in humans. Investigations include collaborations with investigators at several vaccine companies including Genocea Biosciences, Inc., Pfizer, and Merck.
Dr. Darville's lab is examining the role of CD4+ and CD8+ T cells and neutralizing antibody responses in protection from ascending infection and from reinfection using human blood and genital tract tissue samples collected from women at high risk who are followed longitudinally for 12 months. Active investigations with human peripheral blood mononuclear cells include determination of T cell clonotypic expansion after repeated infection and HLA-types associated with susceptibility and protection from disease.
Dr. Darville's team is also examining the role of Th17 cells and T regulatory cells in immunopathogenesis of chlamydial infection using human samples and the mouse model. Recent development of a chlamydial antigen-specific TCR transgenic mouse provides an excellent tool to advance investigations of the adaptive T cell response to chlamydial infection with the ultimate goal to determine mechanisms to induce protective T cell memory.
- Investigation of transcriptional responses and genetic control of development of genital tract disease due to C. trachomatis. Dr. Darville’s research team is seeking to identify the local inflammatory and fibrotic pathways most strongly regulated during Chlamydia trachomatis infection utilizing RNA from blood and endometrial specimens obtained from women with chlamydial pelvic inflammatory disease and women with asymptomatic chlamydial infection. Her team is also working to identify biomarkers for susceptibility to Chlamydia trachomatis infection and progression to tubal pathology.
In addition to the above, active collaborations are being carried out with University of Pittsburgh Medical Center investigators at Children’s Hospital of Pittsburgh, Magee Women’s Research Institute, the University of Pittsburgh Graduate School of Public Health, investigators at Johns Hopkins University, as well as investigators at Genocea, Biosciences, Inc. as part of the UPMC Sexually Transmitted Infections Cooperative Research Center.
Studies funded through the STI CRC include a clinical treatment trial of pelvic inflammatory disease that includes a determination of the benefit of anti-anaerobic therapy on eradication of upper genital tract infection directed by Dr. Harold Wiesenfeld, and an investigation of Mycoplasma genitalium and novel organisms that cause bacterial vaginosis and their role in pelvic inflammatory disease and its sequelae, directed by Dr. Sharon Hillier.