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

• Applicant: Professor Dr. Thomas Miethke
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens ; Immunology
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 363882874

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.

• DFG Programme: Research Grants