Chlamydia trachomatis is the most common bacterial sexually transmitted disease in the developed world with a prevalence approaching 10% in adolescents and young adults. In women C. trachomatis infections ascend into the upper reproductive tract causing scarring that results in infertility and ectopic pregnancy. Antibiotic therapy has been ineffective in addressing the prevalence of the disease making development of a protective vaccine a logical approach to address this common infection. Existing data from the C. muridarum mouse model shows a correlation between a CD4 T cell clones ability to control replication of Chlamydia in epithelial cells in vitro and its ability to protect the reproductive tract in vivo. Similarly, existing vaccine data in the C. muridarum model has shown that not all Chlamydia antigens induce protective immunity. The major challenge for development of a protective Chlamydia vaccine is identifying which of the ~900 Chlamydia proteins is capable of inducing protective immunity. We hypothesize based on existing data that the protective epitopes will be found in the subset of Chlamydia proteins that are processed and presented by infected epithelial cells, generating a CD4 T cell response capable of controlling Chlamydia replication in epithelial cells. CD4 T cell clones that recognize and control C. muridarum replication in epithelial cells are logical tools for identifying candidate vaccine antigens. We propose using our unique epithelial cell lines, existing panel of Chlamdydia- specific CD4 T cell clones, and novel technologic expertise in generating Chlamydia mutants and recombinants to accomplish the following specific aims: #1 to identify six new "epithelial" CD4 epitope-source proteins using recombinant and mutant libraries of C. muridarum combined with genomic sequencing, #2 to investigate the role of epitope abundance on infected epithelial cells as a parameter for CD4 T cell-mediated control of C. muridarum replication in epithelial cells, #3 to investigate the ability of each identified epitope source protein to induce protective vaccine immunity in the C. muridarum mouse model.

Public Health Relevance

Research outlined in this grant proposal will help define the specific proteins included in a future Chlamydia vaccine. Such a vaccine would reduce Chlamydia infections and their complications including infertility and potentially fatal tubal pregnancies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI099307-01
Application #
8280847
Study Section
Vaccines Against Microbial Diseases (VMD)
Program Officer
Hiltke, Thomas J
Project Start
2012-02-15
Project End
2014-01-31
Budget Start
2012-02-15
Budget End
2013-01-31
Support Year
1
Fiscal Year
2012
Total Cost
$194,480
Indirect Cost
$69,480
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202