IRF3 is a novel mediator of cell death during genital Chlamydia infection.

Univ Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

? DESCRIPTION (provided by applicant): Chlamydia trachomatis genital infection is a major cause of pelvic inflammatory disease (PID), resulting in ectopic pregnancy and infertility among women. PID is caused by an overt inflammatory response in the upper genital tract. Bacterial load is an important determining factor in disease progression and transmission from one host to another. An important host response to reduce pathogen load is to initiate an inflammatory cell death. Recently, a novel form of cell death mediated by Interferon Regulatory Factor (IRF3), termed suicide necrosis has been identified in liver Kupffer cells in response to adenovirus and Listeria infection in the mouse model. In our laboratory, we have observed that in female Irf3-/- mice, C. muridarum genital infection results in a dramatically increased early infection (day 4 p.i in the uterine epithelium with intact epithelia, wherein almost every epithelial cell is infected i the entire uterine tract. This is not observed in wild-type (WT) control mice, even under conditions of high inoculum and is associated with significant disruption of epithelia in the areas of infection. Therefore, we hypothesize that IRF3-mediated cell death promotes epithelial disruption in response to chlamydial infection in the genital mucosa, and this innate response is highly effective in reducing pathogen load in vivo. To address this hypothesis, we will achieve the following objectives; (1) Investigate the kinetics and epithelial cell-intrinsic nature of IRF3 dependent cell death response to infection in vivo, and (2) Investigate the potential mediators of IRF3-mediated response during infection. Specific outcome of this R21 study include identification of cellular and molecular components of IRF3-mediated cell death response. This study will provide the foundation for more extensive studies on the role of IRF3 in the protection of female genital tract during Chlamydia and other genital tract infection.