The sequential development of urosepsis and the meaning of the urinary microbiome in a catheter- and urolithiasis-associated urosepsis mouse model.

• Applicant: Dr. Marcus Derigs
• Subject Area: Reproductive Medicine, Urology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 550700580

Urosepsis poses a considerable challenge to global health, accounting for approximately 20% of all sepsis cases and demonstrating a rising incidence. Despite extensive research efforts, urosepsis continues to exhibit a significant mortality rate ranging from 25% to 40%. Individuals with obstructive urolithiasis or urinary catheters are particularly susceptible for urosepsis and face poorer prognoses. However, the pathogenesis of this severe condition and its relationship to contributing factors are not yet fully understood. To address the knowledge gap, we have developed a distinctive mouse model of catheter- and urolithiasis-associated urosepsis. This model involves the percutaneous ultrasound-guided implantation of a catheter and the injection of Proteus mirabilis into the bladder. This creates a continuous nidus for infection, promoting the formation of infection stones and ultimately urosepsis. With access to this innovative in vivo model and our expertise in studying molecular urosepsis biomarkers, we have a valuable opportunity to observe and analyze the step-by-step progression of urosepsis, including the physiological, histological, and molecular changes that occur. Specifically, we aim to investigate the significance of elevated sPD-L1 levels, which our preliminary data suggest may predict adverse outcomes in urosepsis patients. In parallel, we have developed a method to disrupt the natural bacterial composition of the urinary tract in mice through percutaneous antibiotic instillation. This allows us, for the first time, to explore the role of the urinary microbiome in the development and prevention of urosepsis. Our strategy entails comparing the progression of urosepsis in mice with intact urinary microbiomes to those with dysregulated urinary microbiomes. The data collected from this project will be instrumental in improving our understanding of how urosepsis progresses over time and the specific molecular mechanisms implicated. Simultaneously, we will investigate the significance of a new factor, the urinary microbiome, in relation to urosepsis. Ultimately, this project will lay the foundation for the development of novel strategies to treat and prevent urosepsis effectively.

• DFG Programme: WBP Fellowship
• International Connection: Canada
• Participating Institution: Vancouver General Hospital; Prostate Centre
• Host: Professor Dirk Lange, Ph.D.