Chlamydia trachomatis infection is a leading cause of infertility and ectopic pregnancy in women. Although antibiotic therapy eliminates infection, it does not ameliorate established pathology. The protective immunity that develops in response to infection is not long-lived, and animal models indicate that repeated infection elicits worse disease. An improved understanding of the immunopathogenesis of chlamydial disease is needed to develop a rational vaccine strategy to combat the epidemic of chlamydial infection. TLR2-deficient mice do not develop oviduct pathology after chlamydial infection, demonstrating that TLR2 signaling is a key mechanism involved in disease development. We have derived novel plasmid-deficient C. muridarum mutants that retain the ability to infect the murine genital tract, but fail to cause disease. These mutants fail to stimulate TLR2 signaling in cell culture and in vivo and can be used to examine the role of TLR2 in pathogenesis in an immunologically normal host. Based on our observations in the mouse genital tract model, each of the following mechanisms contribute to development of oviduct pathology: 1) TLR2-mediated hyper-activation of innate immune cells leading to an excessive response beyond that required for bacterial clearance, 2) TLR2-mediated hyper-activation of the CD4 T cell response leading to overzealous Th1 activation and induction of Th17 cells that promote tissue-damaging neutrophil responses, 3) alterations in TLR2-independent MyD88-dependent response(s) that lead to prolonged infection and ongoing inflammation which contributes to tissue pathology. We propose the following specific aims: 1. Determine TLR2-mediated effects on innate immune responses during chlamydial infection that promote oviduct pathology.
Aim 2 : Determine the adaptive T cell responses induced in the absence of TLR2 signaling which lead to resolution of chlamydial infection in the absence of tissue damage. We will investigate the role of Tregs in limiting pathology and of Th17 cells in induction of pathology.
Aim 3 : Determine MyD88-dependent innate responses required for efficient chlamydial killing and generation of Th1 adaptive immunity. We will also examine the role of non-TLR2 receptors upstream of MyD88 in chlamydial host defense.

Public Health Relevance

Chlamydia trachomatis is the leading bacterial sexually transmitted pathogen worldwide and a vaccine is urgently needed. In this application we will examine mechanisms of chlamydial immunopathogenesis. Specifically, we will evaluate the mechanisms by which Chlamydia trachomatis infection leads to oviduct damage.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Hiltke, Thomas J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
Schools of Medicine
United States
Zip Code
Poston, Taylor B; Qu, Yanyan; Girardi, Jenna et al. (2017) A Chlamydia-Specific TCR-Transgenic Mouse Demonstrates Th1 Polyfunctionality with Enhanced Effector Function. J Immunol 199:2845-2854
Taylor, Brandie D; Darville, Toni; Ferrell, Robert E et al. (2014) Cross-sectional analysis of Toll-like receptor variants and bacterial vaginosis in African-American women with pelvic inflammatory disease. Sex Transm Infect 90:563-6
Huppler, Anna R; Conti, Heather R; Hernández-Santos, Nydiaris et al. (2014) Role of neutrophils in IL-17-dependent immunity to mucosal candidiasis. J Immunol 192:1745-52
Darville, Toni; Pelvic Inflammatory Disease Workshop Proceedings Committee (2013) Pelvic inflammatory disease: identifying research gaps--proceedings of a workshop sponsored by Department of Health and Human Services/National Institutes of Health/National Institute of Allergy and Infectious Diseases, November 3-4, 2011. Sex Transm Dis 40:761-7
Frazer, Lauren C; Sullivan, Jeanne E; Zurenski, Matthew A et al. (2013) CD4+ T cell expression of MyD88 is essential for normal resolution of Chlamydia muridarum genital tract infection. J Immunol 191:4269-79
Darville, Toni (2013) Recognition and treatment of chlamydial infections from birth to adolescence. Adv Exp Med Biol 764:109-22
Frazer, Lauren C; Scurlock, Amy M; Zurenski, Matthew A et al. (2013) IL-23 induces IL-22 and IL-17 production in response to Chlamydia muridarum genital tract infection, but the absence of these cytokines does not influence disease pathogenesis. Am J Reprod Immunol 70:472-84
Riley, Melissa M; Zurenski, Matthew A; Frazer, Lauren C et al. (2012) The recall response induced by genital challenge with Chlamydia muridarum protects the oviduct from pathology but not from reinfection. Infect Immun 80:2194-203
Taylor, Brandie D; Ness, Roberta B; Darville, Toni et al. (2011) Microbial correlates of delayed care for pelvic inflammatory disease. Sex Transm Dis 38:434-8
Vonck, Rachel A; Darville, T; O'Connell, C M et al. (2011) Chlamydial infection increases gonococcal colonization in a novel murine coinfection model. Infect Immun 79:1566-77

Showing the most recent 10 out of 32 publications