Cellular Immunity to Chlamydua at the Epithelial Interface

Summary

Principal Investigator: RAYMOND MORRIS JOHNSON
Abstract: 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.
Funding Period: ----------------2007 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Perforin is detrimental to controlling [corrected] C. muridarum replication in vitro, but not in vivo
    Raymond M Johnson
    Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
    PLoS ONE 8:e63340. 2013
  2. pmc An atypical CD8 T-cell response to Chlamydia muridarum genital tract infections includes T cells that produce interleukin-13
    Raymond M Johnson
    Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
    Immunology 142:248-57. 2014
  3. pmc Chlamydia muridarum-specific CD4 T-cell clones recognize infected reproductive tract epithelial cells in an interferon-dependent fashion
    Krupakar Jayarapu
    Division of Infectious Diseases, Department of Medicine, Indiana University School of Medicine, 545 Barnhill Drive, 435, Indianapolis, IN 46202, USA
    Infect Immun 77:4469-79. 2009
  4. ncbi The Chlamydia muridarum-induced IFN-β response is TLR3-dependent in murine oviduct epithelial cells
    Wilbert A Derbigny
    Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    J Immunol 185:6689-97. 2010
  5. pmc Chlamydia-specific CD4 T cell clones control Chlamydia muridarum replication in epithelial cells by nitric oxide-dependent and -independent mechanisms
    Krupakar Jayarapu
    Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    J Immunol 185:6911-20. 2010
  6. pmc Plac8-dependent and inducible NO synthase-dependent mechanisms clear Chlamydia muridarum infections from the genital tract
    Raymond M Johnson
    Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    J Immunol 188:1896-904. 2012
  7. pmc PmpG303-311, a protective vaccine epitope that elicits persistent cellular immune responses in Chlamydia muridarum-immune mice
    Raymond M Johnson
    Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
    Infect Immun 80:2204-11. 2012

Scientific Experts

Detail Information

Publications7

  1. pmc Perforin is detrimental to controlling [corrected] C. muridarum replication in vitro, but not in vivo
    Raymond M Johnson
    Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
    PLoS ONE 8:e63340. 2013
    ....
  2. pmc An atypical CD8 T-cell response to Chlamydia muridarum genital tract infections includes T cells that produce interleukin-13
    Raymond M Johnson
    Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
    Immunology 142:248-57. 2014
    ..IL-13-producing Chlamydia-specific CD8 T cells may contribute to immunopathology during C. muridarum genital tract infections based on known roles of TNF-α and IL-13 in scar formation...
  3. pmc Chlamydia muridarum-specific CD4 T-cell clones recognize infected reproductive tract epithelial cells in an interferon-dependent fashion
    Krupakar Jayarapu
    Division of Infectious Diseases, Department of Medicine, Indiana University School of Medicine, 545 Barnhill Drive, 435, Indianapolis, IN 46202, USA
    Infect Immun 77:4469-79. 2009
    ..We discuss our data as they relate to published studies with IFN knockout mice, proposing a straightforward interpretation of the existing literature based on CD4 T-cell interactions with the infected reproductive tract epithelium...
  4. ncbi The Chlamydia muridarum-induced IFN-β response is TLR3-dependent in murine oviduct epithelial cells
    Wilbert A Derbigny
    Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    J Immunol 185:6689-97. 2010
    ....
  5. pmc Chlamydia-specific CD4 T cell clones control Chlamydia muridarum replication in epithelial cells by nitric oxide-dependent and -independent mechanisms
    Krupakar Jayarapu
    Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    J Immunol 185:6911-20. 2010
    ..We discuss our data as they relate to existing knockout mouse studies addressing mechanisms of T cell-mediated control of Chlamydia replication and their implications for intracellular epithelial pathogens in mouse models...
  6. pmc Plac8-dependent and inducible NO synthase-dependent mechanisms clear Chlamydia muridarum infections from the genital tract
    Raymond M Johnson
    Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    J Immunol 188:1896-904. 2012
    ..Although T cell subsets are routinely defined by cytokine profiles, there may be important subdivisions by effector function, in this case CD4(Plac8)...
  7. pmc PmpG303-311, a protective vaccine epitope that elicits persistent cellular immune responses in Chlamydia muridarum-immune mice
    Raymond M Johnson
    Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
    Infect Immun 80:2204-11. 2012
    ....