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

致尿性埃希氏菌CFT073株的细菌Toll/IL-1受体蛋白C(TCPC)损伤Toll样受体(TLR)和炎症小体。TLRs是天然免疫系统中重要的模式识别受体，表达于细胞膜和内膜上。炎症是由结节样受体(NLR)、适配子蛋白凋亡相关的斑点样蛋白(ASC)和Caspase-1组成的复合体，表达于宿主细胞的胞浆中，识别细胞内的病原体等结构。从肾盂肾炎患者中分离出来的泌尿系致病大肠杆菌中，约有40%携带TCPC-基因。目前尚不清楚CFT073是如何诱导该基因以及如何分泌该蛋白质的。因此，该项目旨在了解TCPC的表达调控和蛋白质分泌的机制。这些事件的探索对于了解尿路感染的病理生理学具有高度的相关性，因为TCPC的存在使受感染的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，而导致肾脓肿的是野生型，而不是TCPC缺陷的CFT073菌株。因此，识别TCPC的表达调控及其分泌机制可能为治疗由日益耐药的泌尿系致病大肠杆菌所致的肾盂肾炎提供新的治疗思路。

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.