Chlamydia trachomatis infection remains a major cause of pelvic inflammatory disease, and often leads to fallopian tube injury and infertility in humans. While effective antibiotics are available, asymptomatic infection may ascend to the upper genital tract (GT) and cause irreversible tissue damage before it is discovered. One strategy for avoiding injury to the upper GT is through preventative vaccination. How- ever, the anti-chlamydial CD4 T-helper type 1 (Thl) response that develops to eradicate infection is also thought to participate in upper GT injury. The goal of this project is to identify mechanisms that regulate chlamydial immunity in the upper GT to better understand the basis of upper GT injury. We recently reported that CD4 cells are primarily recruited to the upper but not the lower GT and that Thl attractant chemokines are produced primarily in the upper GT during infection. Based on those find- ings we hypothesize that the ability to recruit T cells differs between the upper and lower GT. We have also found that Thl cells are not the only subset recruited to the GT. Anti-Ch/amydia-specific T cells that produce IL-10 are also recruited to the GT during infection. T cells that secrete IL-10 may interfere with a Thl response and enhance upper GT injury. Therefore, it will be important in validating the hypothesis to determine whether the 11-10 producing T cells that are recruited to the GT can modulate the Thl response against Ch/amyclia. To test this hypothesis we will 1) Identify mechanism(s) that control the enhanced recruitment of Thl CD4 cells to the upper GT, 2) Determine if altering Thl CD4 cell recruitment improves immunity againstChlamydia infection. 3) Determine if IL, IO producing T cells subsets (Th2, Trl) impede anti-chlamydial Th4 immunity. To achieve these goals, we will focus on identifying chemokine and chemokine receptor ligands that mediate Thl cell recruitment to the GT. In addition, we will attempt to boost immunity in the lower GT by the delivery of these Thl-attractant che- mokines to the vaginal region using adenoviruses that secrete Thl-atrractant chemokines. Also, using IL-10 knockout and transgenic mice we will determine whether IL-10 producing T cell subsets influence anti-Chlamydia immunity and the development of upper GT injury,

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI026328-16
Application #
7151466
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Hiltke, Thomas J
Project Start
1988-04-01
Project End
2008-11-30
Budget Start
2006-12-01
Budget End
2008-11-30
Support Year
16
Fiscal Year
2007
Total Cost
$321,508
Indirect Cost
Name
University of California Los Angeles
Department
Pathology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Jiang, Janina; Champion, Cheryl I; Wei, Bo et al. (2013) CD8?CXCR5? T cells regulate pathology in the genital tract. Infect Dis Obstet Gynecol 2013:813238
Jiang, Janina; Kelly, Kathleen A (2012) Isolation of lymphocytes from mouse genital tract mucosa. J Vis Exp :e4391
Kar, Upendra K; Jiang, Janina; Champion, Cheryl I et al. (2012) Vault nanocapsules as adjuvants favor cell-mediated over antibody-mediated immune responses following immunization of mice. PLoS One 7:e38553
Jiang, Janina; Kelly, Kathleen A (2011) Phenotype and function of regulatory T cells in the genital tract. Curr Trends Immunol 12:89-94
Moniz, Raymond J; Chan, Ann M; Gordon, Lynn K et al. (2010) Plasmacytoid dendritic cells modulate nonprotective T-cell responses to genital infection by Chlamydia muridarum. FEMS Immunol Med Microbiol 58:397-404
Kelly, Kathleen A; Chan, Ann M; Butch, Anthony et al. (2009) Two different homing pathways involving integrin ?7 and E-selectin significantly influence trafficking of CD4 cells to the genital tract following Chlamydia muridarum infection. Am J Reprod Immunol 61:438-45
Shimazaki, Kaori; Chan, Ann M; Moniz, Raymond J et al. (2009) Blockade of epithelial membrane protein 2 (EMP2) abrogates infection of Chlamydia muridarum murine genital infection model. FEMS Immunol Med Microbiol 55:240-9
Champion, Cheryl I; Kickhoefer, Valerie A; Liu, Guangchao et al. (2009) A vault nanoparticle vaccine induces protective mucosal immunity. PLoS One 4:e5409
Kickhoefer, Valerie A; Han, Muri; Raval-Fernandes, Sujna et al. (2009) Targeting vault nanoparticles to specific cell surface receptors. ACS Nano 3:27-36
King, M; Poya, H; Rao, J et al. (2009) CXCL13 expression in Chlamydia trachomatis infection of the female reproductive tract. Drugs Today (Barc) 45 Suppl B:125-34

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