Chlamydia pathogenesis

衣原体发病机制

• 批准号: 10665396
• 负责人: GUANGMING ZHONG
• 金额: $ 57.07万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-12 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10665396
• 关键词: Adhesions; Adoptive Transfer; Antigens; Attenuated; B-Lymphocytes; Biological Markers; CD8-Positive T-Lymphocytes; Cellular Assay; Chlamydia; Chlamydia muridarum; Chlamydia trachomatis; Development; Differential Diagnosis; Epithelial Cells; Evaluation; Female; Fibrosis; Gastrointestinal tract structure; Genital; Genitalia; Human; Immobilization; Immune response; Immunity; Infection; Infertility; Interleukin-13; Knowledge; Laparoscopy; Lead; Link; Lymphocyte; MHC Class I Genes; Mammalian Oviducts; Maps; Mus; Pathogenesis; Pathogenicity; Pathologic; Phenotype; Play; Proteome; Role; Sexually Transmitted Diseases; Specificity; Subunit Vaccines; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; Testing; Transgenic Mice; Validation; Woman; base; experimental study; humanized mouse; improved; knockout gene; long-term sequelae; mouse model; prevent; profibrotic cytokine; recruit; reproductive tract; tissue repair; tissue-repair responses; transcriptome sequencing; tubal infertility

Abstract Chlamydia pathogenesis Sexually transmitted infection with Chlamydia trachomatis (CT) is a leading infectious cause of tubal infertility due to the induction of excessive fibrosis observed as adhesion and hydrosalpinx in the female upper genital tract under laparoscopy. Both CT ascending infection and host immune responses likely contribute to the sequelae. Intravaginal inoculation with Chlamydia muridarum (CM) induces hydrosalpinx in mice, which is frequently used for investigating the pathogenic mechanisms of CT. The mouse model reveals a two-hit mechanism for chlamydial induction of hydrosalpinx: The lower genital Chlamydia ascends to the upper genital tract and infects oviduct epithelial cells, causing direct damages, as the 1st hit, and the Chlamydia-induced lymphocytes with a profibrotic phenotype, after recruiting to the oviduct, may provide a 2nd hit to convert the initial damage-triggered tissue repairing into pathological fibrosis. Both hits may be required for chlamydial induction of the sequelae. CM that spreads from the genital tract to the gastrointestinal (GI) tract can most efficiently induce pathogenic CD8+ T cells to provide a 2nd hit for promoting CM pathogenicity in the upper genital tract of mice. Although CT is also frequently detected in the GI tract of women, it is unclear how CT reaches the human GI tract and where CT induces 2nd hits for promoting CT pathogenicity in women. Regardless of how a 2nd hit is induced, we hypothesize that chlamydial antigen-specific T lymphocytes, particularly CD8+ T cells, are able to provide a 2nd hit for promoting chlamydial pathogenicity in the upper genital tract by delivering profibrotic effectors. Since T cells are known to contribute to both chlamydial pathogenesis and immunity, we further hypothesize that pathogenic and protective T cells may recognize both common and distinct CT antigens. We will test these hypotheses by identifying profibrotic effectors of pathogenic CD8+ T cells (Aim I), systematically mapping the antigen specificities of functionally defined pathogenic vs. nonpathogenic CD8+ T cells from mice (Aim II) and identifying T cell antigens in CT-exposed women with or without tubal infertility (Aim III). The information to be obtained will advance our understanding of chlamydial pathogenic mechanisms and improve differential diagnosis of tubal infertility as well as facilitate the development of Chlamydia subunit vaccines.

摘要 衣原体致病 性传播的沙眼衣原体（CT）感染是导致输卵管炎的主要原因。 由于过度纤维化诱导导致不孕，观察到女性上部粘连和输卵管积水 腹腔镜下检查生殖道CT上行感染和宿主免疫反应可能有助于 后遗症阴道内接种小鼠衣原体（CM）可诱导小鼠输卵管积水， 常用于研究CT的致病机制。小鼠模型揭示了一个两击 衣原体诱导输卵管积水的机制：下生殖器衣原体上升至上生殖器 道和感染输卵管上皮细胞，造成直接损害，作为第一次打击，和衣原体诱导 具有促纤维化表型的淋巴细胞，在募集到输卵管后，可以提供第二次打击以将 初始损伤触发组织修复成病理性纤维化。衣原体感染可能需要这两种检测结果 诱发后遗症。从生殖道传播到胃肠道（GI）的CM大多数 有效地诱导致病性CD8+ T细胞，以提供第二次打击，用于促进上部中的CM致病性。 小鼠生殖道。虽然CT也经常在女性的胃肠道中被检测到，但目前还不清楚CT如何 到达人胃肠道，在那里CT诱导第二次攻击，以促进CT在女性中的致病性。 不管第二次攻击是如何诱导的，我们假设衣原体抗原特异性T淋巴细胞， 特别是CD8+ T细胞，能够提供第二次打击，以促进衣原体的致病性， 生殖道通过提供促纤维化效应。由于已知T细胞对衣原体和衣原体感染都有贡献， 发病机制和免疫，我们进一步假设，致病性和保护性T细胞可能认识到这两个 常见和不同的CT抗原。我们将通过识别促纤维化效应物来检验这些假设。 致病性CD8+ T细胞（目的I），系统地绘制功能定义的抗原特异性 来自小鼠的致病性与非致病性CD8+ T细胞（Aim II）和鉴定CT暴露的T细胞抗原 有或没有输卵管不孕症的妇女（目的III）。获得的信息将促进我们的理解 衣原体的致病机制，提高输卵管性不孕症的鉴别诊断，以及促进 衣原体亚单位疫苗的发展。