Chlamydia trachomatis is the leading cause of bacterial sexually transmitted infections worldwide, with annual related costs exceeding $2 billion. In women, untreated infections may progress to serious reproductive tract sequela. Chlamydiae to not appear to express proteins that actively induce disease or tissue damage in the infected host. Rather, the pathology that follows chlamydial infection is the consequence of an aggressive host inflammatory response. Using the C. muridarum mouse model, we have shown that the innate pathogen recognition receptor, TLR2, is essential for development of oviduct pathology. TLR2 gene knock-out (KO) mice do not develop oviduct pathology after chlamydial infection. In addition, plasmid-deficient C. muridarum that cause an infection in mice of normal intensity and duration fail to cause oviduct disease and do not stimulate TLR2. Our data indicate that in the presence of TLR2 signaling, chlamydial infection elicits an immune response of greater magnitude than what is needed and subsequently leads to tissue pathology. In this application we propose to validate our novel model of chlamydial disease where pathology occurs in response to primary chlamydial infection by one or both of the following paths: 1) TLR2-mediated hyper-activation of innate immune cells leading to a response that exceeds what is required for bacterial clearance, ultimately promoting excessive tissue damage and scarring;2) TLR2-mediated hyper-activation of the CD4 T cell response. In addition, we propose to advance our studies beyond the mouse by investigating chlamydial-induced TLR2 signaling and consequential inflammatory responses in human reproductive tract tissues. Completion of our studies will allow us to determine: (1) the effect of chlamydia-induced TLR2-dependent signaling on murine innate immune cell activation in vitro and in vivo, (2) the mechanism by which mouse T cells respond to and resolve a Chlamydia infection without producing oviduct tissue damage, (3) the contribution of chlamydia-induced TLR2 activation to the inflammatory response of human reproductive tract tissue.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI084024-03
Application #
8314063
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
3
Fiscal Year
2011
Total Cost
$307,856
Indirect Cost
Name
University of Pittsburgh
Department
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Zheng, Xiaojing; O'Connell, Catherine M; Zhong, Wujuan et al. (2018) Gene Expression Signatures Can Aid Diagnosis of Sexually Transmitted Infection-Induced Endometritis in Women. Front Cell Infect Microbiol 8:307
Zheng, Xiaojing; O'Connell, Catherine M; Zhong, Wujuan et al. (2018) Discovery of Blood Transcriptional Endotypes in Women with Pelvic Inflammatory Disease. J Immunol 200:2941-2956
Rahman, K Shamsur; Darville, Toni; Wiesenfeld, Harold C et al. (2018) Mixed Chlamydia trachomatis Peptide Antigens Provide a Specific and Sensitive Single-Well Colorimetric Enzyme-Linked Immunosorbent Assay for Detection of Human Anti-C. trachomatis Antibodies. mSphere 3:
Taylor, Brandie D; Zheng, Xiaojing; O'Connell, Catherine M et al. (2018) Risk factors for Mycoplasma genitalium endometritis and incident infection: a secondary data analysis of the T cell Response Against Chlamydia (TRAC) Study. Sex Transm Infect 94:414-420
Rahman, K Shamsur; Darville, Toni; Russell, Ali N et al. (2018) Comprehensive Molecular Serology of Human Chlamydia trachomatis Infections by Peptide Enzyme-Linked Immunosorbent Assays. mSphere 3:
Rahman, K Shamsur; Darville, Toni; Russell, Ali N et al. (2018) Discovery of Human-Specific Immunodominant Chlamydia trachomatis B Cell Epitopes. mSphere 3:
Taylor, Brandie D; Zheng, Xiaojing; Darville, Toni et al. (2017) Whole-Exome Sequencing to Identify Novel Biological Pathways Associated With Infertility After Pelvic Inflammatory Disease. Sex Transm Dis 44:35-41
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
Petrina, Melinda A B; Cosentino, Lisa A; Rabe, Lorna K et al. (2017) Susceptibility of bacterial vaginosis (BV)-associated bacteria to secnidazole compared to metronidazole, tinidazole and clindamycin. Anaerobe 47:115-119
Russell, Ali N; Zheng, Xiaojing; O'Connell, Catherine M et al. (2016) Identification of Chlamydia trachomatis Antigens Recognized by T Cells From Highly Exposed Women Who Limit or Resist Genital Tract Infection. J Infect Dis 214:1884-1892

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