The role of the Chlamydia pneumoniae protein Pmp21 during infection

肺炎衣原体蛋白Pmp21在感染过程中的作用

• 批准号: 37251729
• 负责人: Professor Dr. Johannes H. Hegemann
• 金额: --
• 依托单位: Institut für Funktionelle Genomforschung der Mikroorganismen
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/37251729?language=en
• 关键词: role; Chlamydia; pneumoniae; protein; Pmp21

Chlamydiae are significant human pathogens. Chlamydia trachomatis is responsible for a spectrum of acute ocular and genital tract infections and for chronic diseases that lead to blindness and tubal-factor infertility, such as trachoma and salpingitis, respectively (1). Chlamydia pneumoniae is an important respiratory pathogen associated with 5 to 10 % of community-acquired cases of pneumonia worldwide and a seroprevalence of up to 70%. (2). Chlamydiae are characterized by a unique biphasic developmental cycle that modulates between an extracellular infectious elementary body (EB) and an intracellular noninfectious reticulate body (RB) which replicates within an inclusion in the eukaryotic cell. Despite its relevance very little is known about the molecular mechanism of a chlamydial infection (3, 4). In our RU project we focus on the initial and most important step of the C. pneumoniae infection cycle: the characterization of the molecular interaction of the pathogen with its human host cell during adhesion of the infectious bacteria to and their subsequent internalization by the human cell. Using a recently developed yeast surface display system we identified the polymorphic membrane protein Pmp21 as a second C. pneumoniae adhesin. Work of the last 2 years has revealed that Pmp21 is a bona fide chlamydia adhesin. A detailed deletion and mutational analysis identified 2 short, repetitive amino acid motifs as being necessary for Pmp21 binding to human cells. Pmp21 is relevant for the infection, as pre-incubation of eukaryotic cells with antibody or recombinant protein dose-dependently reduced infection. Pmp21 belongs to a family of 21 proteins and our recent data show that Pmp6 and Pmp20, two other family members, are also important for adhesion and establishment of infection suggesting that possibly the entire Pmp protein family might be involved in this aspect of the C. pneumoniae infection. Biochemical approaches as well as a yeast 2 hybrid screen identified potential human Pmp21-interacting proteins. In future we plan to pursue our efforts to characterize the human receptor. Further characterization of the 2 new adhesins will deepen our understanding of the role of the Pmp protein family in bacterial attachment to and potentially uptake by the human cell. In vivo Pmp21 is found in processed forms and our first data indicate that these forms interact with each other as well as with other Pmp family members. Thus, our goal is to decipher the potential interaction network of Pmp21 to define its role in the infection process. Finally we also want to study the potential role of the Pmp protein family in antigenic variation which would be relevant for immune escape.

衣原体是重要的人类病原体。沙眼衣原体是一系列急性眼部和生殖道感染的罪魁祸首，也是导致失明和输卵管因素不孕的慢性疾病的罪魁祸首，如沙眼和输卵管炎。肺炎衣原体是一种重要的呼吸道病原体，全世界5%至10%的社区获得性肺炎病例和高达70%的血清阳性率有关。(2)。衣原体具有独特的双相发育周期，在细胞外感染性基本体(EB)和细胞内非感染性网状小体(RB)之间进行调节，后者在真核细胞中的包涵体内复制。尽管与此相关，但人们对衣原体感染的分子机制知之甚少(3，4)。在我们的RU项目中，我们专注于肺炎衣原体感染周期的最初也是最重要的步骤：在感染细菌与人类细胞黏附以及随后它们被人类细胞内化的过程中，病原体与其宿主细胞的分子相互作用的表征。利用最近开发的酵母表面展示系统，我们将多态的膜蛋白Pmp21鉴定为第二个肺炎链球菌粘附素。过去两年的研究表明，Pmp21是一种真正的粘附素衣原体。详细的缺失和突变分析确定了Pmp21与人类细胞结合所必需的两个短的、重复的氨基酸基序。Pmp21与感染有关，因为真核细胞与抗体或重组蛋白预先孵育可剂量依赖地减少感染。Pmp21属于一个由21个蛋白组成的家族，我们最近的数据表明，另外两个家族成员Pmp6和Pmp20也对黏附和感染的建立起重要作用，这表明整个PMP蛋白家族可能参与了肺炎衣原体感染的这一方面。生化方法和酵母2杂交种筛选出了潜在的人类Pmp21相互作用蛋白。在未来，我们计划继续努力确定人类受体的特征。对这两个新粘附素的进一步表征将加深我们对PMP蛋白家族在细菌附着和潜在地被人类细胞摄取中的作用的理解。在体内，Pmp21以加工的形式被发现，我们的第一个数据表明这些形式相互作用，以及与PMP家族的其他成员相互作用。因此，我们的目标是破译Pmp21潜在的相互作用网络，以确定其在感染过程中的作用。最后，我们还想研究PMP蛋白家族在抗原变异中的潜在作用，这可能与免疫逃逸有关。