Urological Biology

Urinary tract infection (UTI) is caused by a broad variety of different microbes. We are interested in how bacterial behaviours at the host/pathogen interface facilitate virulence and persistence at the cellular and molecular level, focusing on a number of different pathogens including Escherichia coli, Klebsiella pneumoniae, Enterococcus faecalis, Proteus mirabilis and Pseudomonas aeruginosa, among others. We study various bacterial behaviours, and are particularly intrigued by the phenomenon of invasion, whereby bacteria shelter inside cells in the bladder wall to form stubborn reservoirs that resist treatment. Given that many of the same species can be isolated from healthy bladders as part of the normal bladder "microbiome", we want to understand what characteristics distinguish the pathogens from their more friendly counterparts, and how the two camps interact. Finally, the host generally has many ways to counter invading bacteria, but this is not well studied in human cells in the UTI context.

It is well known that 20-30% of UTIs come back even despite treatment, and the bacteria have evolved a number of tricks to evade antibiotics. Even bacteria that can be killed by a particular antibiotic in a test tube can thrive in the body, at least temporarily but long enough to regroup, in high doses of drug by switching on emergency genetic programmes (a phenomenon known as ‘phenotypic resilience’). Using more physiological human microtissue models, we aim to use the science of transcriptomics, proteomics and metabolomics to pinpoint how UTI bacteria escape killing under these circumstances, which could lead to novel drug targets or alternative therapies. We are also studying biofilms, which are naturally treatment-resistant communities of microbes, often comprised of multiple species, that are problematic in a variety of chronic infections but are not as well understood in UTI. 

While many significant advances have been made in animal models, there are key species-specific differences in urinary tract structure, function and immunity whose consequences for patient relevance are unknown. In recent years, we have developed innovative human urothelial microtissue models to understand bladder biology. The most recent version, called 3D-UHU, is fully stratified to human thickness (up to 7-8 layers, as opposed to the mouse urothelium, which only expresses three); is terminally differentiated with correct biomarkers; has robust barrier function; and is fully urine-tolerant, allowing the exposure of bacteria or materials in their native environment. 3D-UHU also elaborates a protective glycosaminoglycan layer on the luminal side, secretes key cytokines in response to infection and undergoes physiological cell shedding, which is a well-known bladder defence mechanism. This in turn disrupts urothelial barrier function, which is a dangerous situation for the host.

3D-UHU underpins many of our infection studies in the lab. We are also adapting the model so it experiences flow and stretch, two important mechanical activities in the bladder, and incorporating catheter material as a model for catheter-induced UTI, a serious problem globally. Because UTI involves a journey from the gut to the bladder, and sometimes from bladder to kidney, we are creating a linked “pelvis-on-a-chip” comprised of individual organoid-based microtissues to study ascending infection. Finally, we have adapted the model as a testbed for understanding urothelial cancers and trialling new treatments for this highly pervasive malignant disease.

We collaborate with engineering colleagues at UCL and Oxford to develop new cures for UTI and bladder cancer, based on increasing the tissue penetration of existing drugs. One of our collaborative candidates is being taken forward by the UCL spinout company AtoCap Ltd. We are also performing fundamental research to discover entirely new drug targets.

If you are a patient or member of the public interested in recurrent, chronic or treatment-resistant UTI, the Chronic UTI Campaign UK is an excellent source of information.