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Project

The role of the TRP channels in the defense against bacterial urinary tract infections.

Urinary tract infections (UTIs) are amongst the most common bacterial infections in humans, requiring millions of antibiotic prescriptions annually. Available therapies have not evolved significantly in recent years, do not prevent recurrences, and are challenged by rising antibiotic resistance. The field lacks a thorough understanding of the protective host immunity and the impact of bladder function on UTI susceptibility. As such, there is an urgent need for novel strategies for the treatment and prevention of UTIs. The general aim of this dissertation is to obtain a better understanding of the interaction between the host and the pathogen, the urothelium and uropathogenic Escherichia coli (UPEC). 

 

To this end, we have optimized a murine UTI model, using bioluminescence imaging to enable the non-invasive, longitudinal follow up of the bacterial load. In a next step, this model was used to investigate UTI clearance kinetics in vivo in Tlr4 and TrpV4-deficient mice. In vivo and in vitro results did not confirm the role of these receptors in the responses to a UPEC challenge. 

We have demonstrated that a viable bacterial suspension triggers calcium responses in urothelial cells. The origin of the observed calcium responses was an IP3-mediated release of calcium from the intracellular stores via the PLC-pathway. The precise target and downstream effects of the calcium responses remain to be investigated.

Finally, we have investigated the local analgesic effect of phenazopyridine (PAP) on the lower urinary tract. We have shown that PAP at therapeutically relevant concentrations inhibits TRPM8 in afferent pathways, and can thus provide pain relief, especially under pathological conditions such as bladder pain syndrome or chronic inflammation.

 

In conclusion, we have investigated UTI susceptibility, urothelial responses and the involvement of TRP channels by challenging cells and animals with UPEC. 

Date:2 Aug 2018 →  29 Jun 2022
Keywords:urinary tract, infection, bacteria, ion channels, TRP channels
Disciplines:Laboratory medicine, Other basic sciences, Other health sciences, Other translational sciences, Other medical and health sciences
Project type:PhD project