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。

• 批准号: 9310325
• 负责人: Uma M Nagarajan
• 金额: $ 22.8万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-08 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9310325
• 关键词: Address; Adenovirus Infections; Alpha Cell; Apoptosis; Area; Bacteria; Biochemical; Bone Marrow; Cell Culture Techniques; Cell Cycle Kinetics; Cell Death; Cell Membrane Permeability; Cell Proliferation; Cell membrane; Cells; Cellular Structures; 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; 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' 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

 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（由申请人提供）：沙眼衣原体生殖器感染是盆腔炎（PID）的主要原因，导致异位妊娠和不孕症的妇女。PID是由上生殖道的明显炎症反应引起的。细菌负荷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。减少病原体负荷的重要宿主反应是引发炎性细胞死亡。最近，在小鼠模型中，已经在肝枯否细胞中鉴定了由干扰素调节因子（IRF 3）介导的称为“自杀性坏死”的新型细胞死亡形式，其响应于腺病毒和李斯特菌感染。在我们的实验室中，我们观察到在雌性Irf 3-/-小鼠中，C.鼠伤寒生殖器感染导致具有完整上皮的子宫上皮中早期感染（感染后第4天）显著增加，其中几乎每个上皮细胞在整个子宫道中被感染。这在野生型（WT）对照小鼠中没有观察到，即使在高接种量的条件下也是如此，并且与区域中上皮细胞的显著破坏有关。 感染因此，我们假设IRF 3介导的细胞死亡促进生殖器粘膜中衣原体感染引起的上皮破坏，并且这种先天性反应在降低体内病原体负荷方面非常有效。为了验证这一假设，我们将实现以下目标：（1）研究IRF 3的动力学和上皮细胞内在性质 体内感染的依赖性细胞死亡反应，和（2）研究感染期间IRF 3介导的反应的潜在介质。这项R21研究的具体结果包括鉴定IRF 3介导的细胞死亡应答的细胞和分子组分。本研究为进一步深入研究IRF 3在衣原体及其他生殖道感染中对女性生殖道的保护作用奠定了基础。