Molecular function and biological importance of the protease CPAF during infection of human cells by Chlamydia

沙眼衣原体是一种专性细胞内细菌，在人感染过程中引起被感染细胞的巨大变化和实质性病理。虽然许多宿主细胞对衣原体感染的反应已经被描述，但细菌效应物的分子身份是不确定的，它们对宿主细胞反应的重要性也只是不完全了解。我们已经确定了衣原体蛋白酶CPAF作为宿主细胞操纵和细胞致病性的重要介质。在拟议的项目中，我们的目标是对CPAF在衣原体感染人类细胞中的作用和重要性进行分子理解。以下细胞系统从我们的工作中作为CPAF的靶点：先天免疫信号（NF-κB， ERK）；细胞活力/细胞死亡机制；宿主细胞中的蛋白质翻译；泛素-蛋白酶体系统。考虑到新发现的人类CPAF底物和新认识的蛋白酶特征，我们将分析CPAF以何种方式改变这些系统的活性，以及这在感染期间如何影响宿主细胞。此外，在衣原体样细菌中发现了CPAF同源物，这些细菌并不主要感染人类。通过对这些同源物的比较分析，将有可能获得CPAF的分子和细胞生物学活性与人类感染能力有关的信息。我们相信，了解CPAF生物学将是了解衣原体在人类中的致病性的重要一步。

Chlamydia trachomatis is an obligate intracellular bacterium that causes massive changes to the infected human cell and substantial pathology during human infection. Although many host cell responses to chlamydial infection have been described, the molecular identity of bacterial effectors is uncertain and their importance for the host cell response is understood only incompletely. We have identified the chlamydial protease CPAF as an important mediator of host cell manipulation and cytopathogenicity. In the proposed project we aim at a molecular understanding of the role and importance of CPAF in the infection of human cells by Chlamydia. The following cellular systems emerge from our work as targets of CPAF: innate immune signalling (NF-κB, ERK); cell viability/cell death machinery; protein translation in the host cell; the ubiquitin-proteasome system. Considering newly identified human CPAF substrates and newly recognised characteristics of the protease, we will analyse in what way CPAF alters the activity of these systems and how this affects the host cell during infection. Furthermore, CPAF orthologues have been identified in Chlamydia-like bacteria that do not primarily infect humans. By comparative analysis of these orthologues it will be possible to obtain information which molecular and cell biological activity of CPAF is associated with the capacity for human infection. We believe that understanding CPAF biology will be an important step to the appreciation of chlamydial pathogenicity in humans.