Kidney Research Northwest

How does bacterial infection cause ureteric dysfunction and contribute to kidney damage

Researcher(s): Dr Rachel Floyd, Dr Ted Burdyga, Prof Susan Wray, Dr Craig Winstanley

The urinary tract is a highly adapted system that produces, stores, and eliminates urine. In humans and most mammals it is composed of two kidneys, two ureters, the urinary bladder, two sphincter muscles, and the urethra. The ureters are approximately 200 to 250 mm (8 to 10 inches) long and the regular contractions of the muscle tissue in the walls of the ureters rhythmically force the urine downwards. Small amounts of urine are emptied into the bladder from the ureters about every 10 to 15 seconds. As with most bodily processes, things can go wrong. An infection anywhere from the kidneys to the ureters to the bladder to the urethra is categorised as a urinary tract infection. Urinary tract infection (UTI) is a common cause of morbidity pre and post-transplantation and recurrent UTI also presents a significant clinical problem to doctors in general practice. Infection affects the ability of the ureters to contract causing reflux of urine back to the kidneys and resultant tissue damage. This work was in part directed at obtaining data to give us a clearer idea of what occurs during infection to interfere with normal urinary tract physiology.

Even though over 80% of UTI are caused by E. coli, nothing was previously known about how this common bacterium interacts with the host cells of the ureter or even how normal contraction is regulated. We have investigated the molecular effectors in human and rat ureters that may be targeted by E.coli during infection to promote abnormal contractile activity. Our studies have used methods such as real time imaging of green fluorescent E.coli which are designed to glow green so that during infection we can monitor not only their effect on normal function but also track their progress through the different layers of the tissue as the infection progresses.

All E.coli possess distinct virulence factors which include molecules that allow the bacteria to avoid detection by the host immune system and in some cases inhibit its activity and also to enter or exit the host cells in a distinct area of the body such as the gut, bladder or throat. We are currently studying which virulence factors are important in the initial stages of establishing an infection in the ureters, by using strains of E.coli that have one virulence factor deleted from their genetic blueprint. Preliminary data using strains of E.coli that are ‘deletion mutants’ for adhesion factors that allow E.coli to stick to the cell surface show that the binding of bacteria to its host is a critical factor in causing impaired peristalsis.

In February 2010 we published an article in a peer-reviewed international journal, the American Journal of Physiology-Renal Physiology. In this manuscript, our data show for the first time that E.coli colonization targets 2 specific mechanisms associated with channels in the muscle cell membrane, that are primarily responsible for regulating the contractility of human and rat ureters in both health and other disease states.

Our future studies will focus on determining the specific molecular targets that clinical strains of uropathogenic E. coli seek out during interaction with the host cells and how the message is transmitted through the urothelial cells that line the ureters using a combination of intact tissue and cultured cell models of urinary tract infection. It is hoped that these studies will allow us to determine the mechanisms by which infection impairs normal ureteric function and how this may be exploited. This work has brought us closer to our goal in either preventing the cause of urinary tract infections or being better able to treat them. In addition our increased knowledge of the interactions of E.coli with mediators of normal physiology of the ureter may also yield insights of relevance to other clinical problems affecting the urinary tract.

Research Partners
Liverpool University The Royal Liverpool and Broadgreen University Hospital
Supported by
Mitchell Charlesworth