Chlamydia trachomatis has a marked tissue tropism, replicating almost exclusively in epithelial cells lining the reproductive tract. The Chlamydia muridarum mouse model for human C. trachomatis disease has clearly demonstrated that T cells mediate protective immunity against reproductive tract infection. The central hypothesis of the grant is that Chlamydia-specific T cells responsible for sterilizing immunity interact with infected reproductive tract epithelial cells. Surprising little is known about T cell interactions with Chlamydia-infected epithelial cells. The major goal of the project is to understand which Chlamydia-specific T cell subsets eliminate infected epithelial cells from the reproductive tract, and how they accomplish that desired endpoint. Specifically the grant proposes to 1) To identify T cell subsets that interact with Chlamydia-infected oviduct epithelial cells to mediate sterilizing immunity, and identify the effector mechanism employed, 2) To define the specific antigen presentation pathways utilized by epithelial cells to present the Chlamydia antigens, 3) To determine the costimulatory and coinhibitory contributions of infected epithelial cells to activation of protective Chlamydia-specific T cells. To address these specific aims, unique oviduct epithelial cell lines have been generated to serve as antigen presenting cells for isolating Chlamydia- specific T cell lines. Understanding how T cells interact with infected epithelial cells to mediate sterilizing immunity may contribute to vaccine development by identifying surrogate markers for protective immunity that can be exploited in future vaccine trials. Chlamydia trachomatis infections of the reproductive tract have been the most commonly diagnosed bacterial STD in the United States since the early 1990's. In women, C. trachomatis infections commonly ascend into the Fallopian tubes causing infertility and ectopic pregnancies. Standard public health measures have not significantly decreased the incidence of C. trachomatis infections, therefore development of a Chlamydia vaccine would be a major step forward in public health. This grant proposes to contribute toward rational development of a Chlamydia vaccine by investigating how protective immunity works in the reproductive tract. Defining what protective T cells look like, and how they function, will be critical for designing and assessing future Chlamydia candidate vaccines. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI070514-02
Application #
7458802
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Hiltke, Thomas J
Project Start
2007-07-01
Project End
2011-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
2
Fiscal Year
2008
Total Cost
$356,704
Indirect Cost
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
Johnson, Raymond M; Brunham, Robert C (2017) Reply to Vicetti Miguel et al., ""Setting Sights on Chlamydia Immunity's Central Paradigm: Can We Hit a Moving Target?"" Infect Immun 85:
Johnson, Raymond M; Kerr, Micah S (2015) Modeling the transcriptome of genital tract epithelial cells and macrophages in healthy mucosa versus mucosa inflamed by Chlamydia muridarum infection. Pathog Dis 73:ftv100
Johnson, Raymond M; Kerr, Micah S; Slaven, James E (2014) An atypical CD8 T-cell response to Chlamydia muridarum genital tract infections includes T cells that produce interleukin-13. Immunology 142:248-57
Johnson, Raymond M; Kerr, Micah S; Slaven, James E (2013) Perforin is detrimental to controlling [corrected] C. muridarum replication in vitro, but not in vivo. PLoS One 8:e63340
Johnson, Raymond M; Yu, Hong; Kerr, Micah S et al. (2012) PmpG303-311, a protective vaccine epitope that elicits persistent cellular immune responses in Chlamydia muridarum-immune mice. Infect Immun 80:2204-11
Johnson, Raymond M; Kerr, Micah S; Slaven, James E (2012) Plac8-dependent and inducible NO synthase-dependent mechanisms clear Chlamydia muridarum infections from the genital tract. J Immunol 188:1896-904
Jayarapu, Krupakar; Kerr, Micah; Ofner, Susan et al. (2010) Chlamydia-specific CD4 T cell clones control Chlamydia muridarum replication in epithelial cells by nitric oxide-dependent and -independent mechanisms. J Immunol 185:6911-20
Derbigny, Wilbert A; Johnson, Raymond M; Toomey, Katherine S et al. (2010) The Chlamydia muridarum-induced IFN-? response is TLR3-dependent in murine oviduct epithelial cells. J Immunol 185:6689-97
Jayarapu, Krupakar; Kerr, Micah S; Katschke, Adrian et al. (2009) Chlamydia muridarum-specific CD4 T-cell clones recognize infected reproductive tract epithelial cells in an interferon-dependent fashion. Infect Immun 77:4469-79