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

IRF3 是生殖器衣原体感染期间细胞死亡的新型介质。

基本信息

批准号：
9092280
负责人：
Uma M Nagarajan
金额：
$ 19万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-08 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9092280
关键词：
Address Adenovirus Infections Apoptosis Area Bacteria Biochemical Bone Marrow Cell Culture Techniques Cell Cycle Kinetics Cell Death Cell Membrane Permeability Cell Proliferation Cell membrane Cells Chimera organism Chlamydia Chlamydia Infections Chlamydia trachomatis Data Disease Outcome Disease Progression Disease susceptibility Ectopic Pregnancy Endometrial Epithelial Epithelial Cells Epithelium Female Foundations Future Gene Expression Genital system Goals Growth Host Defense Mechanism Human IRF3 gene Immune response Infection Infertility Inflammatory Inflammatory Response Integration Host Factors Interferon-alpha Interferons Kinetics Kupffer Cells Laboratories Lead Leukocytes Listeriosis Liver Mediating Mediator of activation protein Medical Modeling Molecular Mucous Membrane Mus Nature Necrosis Outcome Pathway interactions Pelvic Inflammatory Disease Peritoneal Macrophages Phenotype Predisposition Propidium Diiodide Proteins Role Signal Transduction Suicide Surface Tissue Harvesting Tissue imaging Treatment Cost Variant Viral Load result Woman Women&apos s Health Youth burden of illness cell type disease transmission fluorescence imaging genital infection in vivo mouse model novel pathogen potential biomarker public health relevance receptor reproductive reproductive tract response transcription factor transmission process vaccine trial

项目摘要

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.

描述(申请人提供)：沙眼衣原体生殖器感染是导致盆腔炎的主要原因，导致妇女异位妊娠和不孕。PID是由上生殖道的一种明显的炎症反应引起的。细菌载量是疾病进展和从一个宿主传播到另一个宿主的重要决定因素。减少病原体负荷的一个重要的宿主反应是启动炎性细胞死亡。最近，在小鼠肝枯否细胞对腺病毒和李斯特菌感染的反应中，发现了一种由干扰素调节因子(IRF3)介导的新的细胞死亡形式，称为“自杀性坏死”。在我们的实验室中，我们观察到在雌性IRF3-/-小鼠中，生殖器感染鼠的早期感染显著增加(第4天P.I)，在子宫上皮细胞完好的情况下，几乎每个上皮细胞都感染了整个子宫。这在野生型(WT)对照组小鼠中没有观察到，即使在高接种量的条件下也是如此，并且与该区域的上皮细胞显著破坏有关感染的可能性。因此，我们假设IRF3介导的细胞死亡促进了生殖器黏膜中衣原体感染的上皮性破坏，这种固有的反应在降低体内病原体负荷方面非常有效。为了解决这一假设，我们将实现以下目标：(1)研究IRF3的动力学和上皮细胞固有性质以及(2)研究感染过程中IRF3介导的反应的潜在介体。这项R21研究的具体结果包括鉴定IRF3介导的细胞死亡反应的细胞和分子成分。本研究为更广泛地研究IRF3在衣原体感染和其他生殖道感染中对女性生殖道的保护作用奠定了基础。