Innate lymphocytes in the female genital tract and their role in chlamydial infection

女性生殖道中的先天淋巴细胞及其在衣原体感染中的作用

• 批准号: 320257215
• 负责人: Professor Dr. Georg Häcker
• 金额: --
• 依托单位: Department für Medizinische Mikrobiologie, Virologie und Hygiene
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/320257215?language=en
• 关键词: Innate; lymphocytes; female; genital; tract

The role of populations of innate lymphocytes (ILCs) has been investigated at a number of mucosal surfaces and some of their activities have been worked out, for instance in the intestine and the respiratory tract. The female genital tract also is a substantial mucosal surface that serves as the site of initial infection for a number of pathogens. Very little is known about ILC-populations in the lower and higher genital tract in women and female mice, and almost no functional information is available. Chlamydia trachomatis is the most frequent bacterial agent of sexually transmitted disease with a high prevalence in young women. C. trachomatis initially infects the genital tract through the cervical epithelium but can ascend into the uterus and the oviducts and cause pelvic inflammatory disease, leading to substantial tissue damage. In a mouse model, chlamydial infection is during the first week characterised by a neutrophilic infiltrate, which is later replaced by T cells. We used the mouse model of intravaginal infection with C. muridarum in reporter mice that permit the definition of classical (c)NKs, ILC1s and ILC3s. We found that cNKs are the largest population of ILCs at steady state in the genital tract, with smaller populations of ILC1s and ILC3s. Four days after infection with C. muridarum we observed a massive expansion of ILC1s and smaller, still substantial, expansions of cNKs and ILC3s. Substantial production of IFN-gamma from cNKs and of TNF from ILC1s was observed at that point. We hypothesise that this strong response early in the infection contributes to the shape of the immune response to Chlamydia and to development and outcome of the infection. In this project we will test this hypothesis by pursuing three specific goals. First, we will characterize the subpopulations of ILCs in the genital tract in terms of cellular composition and characteristics, activity and effector capacity. Secondly, we will analyse the upstream signals activating these ILCs during chlamydial infection. We will establish which populations of cells in the genital tract produce key cytokines during chlamydial infection (IL-12, -15 and -18), and which effects these cytokines have on ILC expansion and activity. Thirdly, using genetic models of ILC-depletion we will endeavour to work out the importance of ILCs and ILC-subpopulations for chlamydial replication and anti-chlamydial defence, for the shape of the myeloid and lymphocytic immune response, the CD4 memory response and for the extent of tissue damage. We believe that the results of this project will permit insight not only into the ways how ILCs contribute to the response to an important mucosal pathogen but also will provide information on the organization of the early immune response at this relevant site of infection.

先天性淋巴细胞（ILC）群体的作用已经在许多粘膜表面进行了研究，并且已经确定了它们的一些活动，例如在肠道和呼吸道中。女性生殖道也是一个实质性的粘膜表面，作为许多病原体的初始感染部位。关于女性和雌性小鼠下生殖道和上生殖道中的ILC群体知之甚少，几乎没有功能信息。沙眼衣原体是性传播疾病中最常见的细菌病原体，在年轻女性中的发病率很高。C.沙眼最初通过子宫颈上皮感染生殖道，但可上升到子宫和输卵管，引起盆腔炎，导致严重的组织损伤。在小鼠模型中，衣原体感染在第一周以嗜中性粒细胞浸润为特征，随后被T细胞取代。我们采用小鼠阴道内感染C.在报告小鼠中的muridarum，其允许经典（c）NK、ILC 1和ILC 3的定义。我们发现，cNKs是生殖道中处于稳态的ILC的最大群体，ILC 1和ILC 3的群体较小。感染C.我们观察到ILC 1的大量扩增和较小的、仍然大量的cNK和ILC 3的扩增。此时观察到cNK产生大量IFN-γ，ILC 1产生大量TNF。我们假设，这种强烈的反应在感染早期有助于形成免疫反应的衣原体和发展和感染的结果。在这个项目中，我们将通过追求三个具体目标来测试这个假设。首先，我们将描述生殖道ILC亚群的细胞组成和特性，活性和效应能力。其次，我们将分析在衣原体感染过程中激活这些ILC的上游信号。我们将确定在衣原体感染期间生殖道中哪些细胞群产生关键细胞因子（IL-12、IL-15和IL-18），以及这些细胞因子对ILC扩增和活性的影响。第三，使用ILC耗竭的遗传模型，我们将努力研究ILC和ILC亚群对衣原体复制和抗衣原体防御、骨髓和淋巴细胞免疫应答的形状、CD 4记忆应答和组织损伤程度的重要性。我们相信，该项目的结果将允许洞察的方式不仅ILC如何有助于响应一个重要的粘膜病原体，但也将提供信息的组织在这个相关的感染部位的早期免疫反应。