衣原体感染与细胞程序性坏死机制相互作用的研究

衣原体感染与宿主细胞死亡机制的相互作用对衣原体感染致病、宿主控制清除感染均有深刻影响，是近年来国际上衣原体感染研究的热点之一。作为细胞死亡机制研究领域最新前沿，程序性坏死（programmed necrosis）是一种不同于凋亡和自噬的程序性死亡方式，但其与衣原体感染的关系目前还不清楚。本课题的前期实验提示了衣原体感染与程序性坏死存在密切的联系。在原有工作基础上，本研究利用细胞感染模型及动物感染模型(基因敲除小鼠等)，对衣原体感染与程序性坏死机制的关系作一个比较深入的剖析，包括衣原体感染如何启动程序性坏死发生、其通路中间的关键环节以及下游效应分子如何发挥作用，并初步探讨调控程序性坏死通路对衣原体复制增殖水平、感染炎症效应等的影响。研究结果可以丰富衣原体与宿主相互作用的基本理论，加深理解衣原体感染致病与细胞死亡调控分子机制的关系，从而为研发临床有效防治衣原体感染致病的手段提供新的线索。

Chlamydia infection is one of the huge problems of the public health globally. The bottle neck of controling and preventing Chlamydia infection arises from our limited understanding of Chlamydia-host interplays. As obligate intracellular bacteria, Chlamydia can replicate only in the infected host-cell, and in the end of their intracellular life cycle they have to be released for dissemination. The outcome of Chlamydia infection will therefore depend on the interaction of Chlamydia and cell death pathways. Apoptosis, autophagy and necrosis are three different major types of cell death. The roles of apoptosis and autophagy in Chlamydia infection have been well studied. Necrosis was originally considered a nonspecific mode of cell death. However, recent cutting-edge studies demonstrated tightly intrinsic-cellular-pathway-controlled necrosis (programmed necrosis) was triggered by multiple types of stimuli. For instances, TNF can induce programmed necrosis by initiating RIP1 and RIP3 interaction to form a necrosome, which has been identified as a key mediator of caspase-independent cell death; Moreover, Lipopolysaccharide (LPS), a component of the cell walls of Gram-negative bacteria, interacts with TLR4 and induces macrophage programmed necrosis when caspase-8 activity is inhibited. TRIF and RIP3 interaction is the key event in this LPS-triggering process and forms another type of necrosome. In both cases of TNF or LPS stimulation, ROS is the putative key effector at the downstream of the necrosomes, executing the cellular necrosis. Notably, recent advancements indicates programmed necrosis may be of importance equal to that of apoptosis: these two cell-death pathways may suppress each other, and programmed necrosis also serves as an alternative when caspase-dependent apoptosis is inhibited or absent. As a new identified mechanism of cell death, it is elusive yet about the role of programmed necrosis in Chlamydia infection. Our pilot experiments showed programmed necrosis was closely related to Chlamydia infection. Based on the preliminary data, we will try to dissect systematically the relatiohship of programmed necrosis and Chlamydia infection by cellular infectious models and animal infectious models (knock-out mice), and try to answer the following questions: How does Chlamydia infection initiate the programmed necrosis? What is the key signalling complexes and downstream effector? What is the biological significances of programmed necrosis to Chlamydia replication, inflammation and patholoy in Chlamydia-infected host? Exploration to the answers of those questions might provide new insights into Chlamydia-host interplays and deepen our understandings of the relathionship between cell death mechanisms and Chlamydia infection, and thus give novel clues to develop effective prophylactic and therapeutic approaches to Chlamydia infection.