Regulation of expression and mechanism of secretion of the Toll/Interleukin-1 receptor protein C of uropathogenic E. coli

尿路致病性土栖大肠杆菌菌株CFT 073的细菌Toll/白细胞介素-1受体蛋白C（TcpC）损害Toll样受体（TLR）和炎性小体。TLR是先天免疫系统的关键模式识别受体，并在细胞膜和内体膜上表达。炎性小体是由NOD样受体（NLR）、衔接蛋白（adaptor protein）、凋亡相关斑点样蛋白（ASC）和半胱天冬酶-1组成的复合物，在宿主细胞的胞质溶胶中表达，并识别胞内病原体等结构。约40%的尿路致病性E.分离自肾盂肾炎患者的大肠杆菌菌株携带tcpC基因。目前尚不清楚该基因是如何被诱导的，以及CFT 073如何分泌蛋白质。因此，该项目旨在了解TcpC表达的调节以及参与蛋白质分泌的机制。这些事件的探索对于尿路感染的病理生理学理解具有高度相关性，因为TcpC的存在使受感染实验动物的尿液和肾脏中的细菌负荷增加了两到三个数量级，并且野生型而不是tcpC缺陷型CFT 073菌株负责诱导肾衰竭。 因此，鉴定TcpC表达的调节及其分泌机制可能导致对由日益耐药的尿路致病性E.大肠杆菌菌株。

The bacterial Toll/Interleukin-1 receptor protein C (TcpC) of the uropathogenic Escherischia coli strain CFT073 impairs Toll-like receptors (TLR) and the inflammasome. TLRs are crucial pattern recognition receptors of the innate immune system and expressed at the cellular and endosomal membrane. The inflammasom is a complex consisting of NOD-like Receptors (NLR), the adaptor protein apoptosis-associated speck-like protein (ASC) and Caspase-1, is expressed in the cytosol of host cells and recognizes amongst other structures intracellular pathogens. Around 40% of uropathogenic E. coli strains, which were isolated from patients suffering from pyelonephritis, harbor the tcpC-gene. It is unknown how the gene is induced and how the protein is secreted by CFT073. The project therefore aims to understand the regulation of TcpC expression and the mechanism involved in the secretion of the protein. The exploration of these events is of high relevance for the pathophysiologic understanding of urinary tract infections, since the presence of TcpC increases the bacterial burden by two to three orders of magnitude in urine and kidneys of infected experimental animals and the wildtype, but not the tcpC-deficient CFT073 strain, is responsible for the induction of kidney abscesses. Thus, identification of the regulation of TcpC expession and its secretion mechanism could lead to novel treatment concepts for pyelonephritis caused by increasingly antibiotic-resistant uropathogenic E. coli strains.