1. A healthy bladder and urethra

The yellow part is the urine and the pink area is the urothelium – the tissue lining of the bladder and parts of the urethra.

The urothelium is made up of epithelial cells – seen here with a purple cell nucleus.

The urothelim is about five cells deep. Experts think it takes about 100 days for a cell at the bottom to move to the top.

a health bladder and urethra

2. Early phase of a urinary infection

The normal bladder is not sterile and contains at least 550 different species of bacteria. It has plenty of  microbes – bacteria, fungi and viruses – swimming around in the urine but they are in comfortable balance with the body and not causing symptoms.

But some microbes are pathogens – bacteria that can cause infections or disease.

Bacilli are just one type of bacteria that can cause a urinary infection – they are shown here in green swimming in the urine.

A normal bladder has plenty of microbes swimming around in the urine but they are in comfortable balance with the body and not causing symptoms.

Early phase of a urinary infection

3. Changes to the tissue lining of the bladder

The bacilli bacteria have changed form and have adopted the shape of round cocci – spherical, ovoid or round shape. They have penetrated down to the base of the urothelium and some have entered the cells. This is called intracellular colonisation.

When infection causing bacteria enter cells they go into a dormant state, similar to hibernation, and so do not divide. They can live in these cells for long periods of time and move into fresh cells – they are called ‘persisters’.

Persisters are only affected by antibiotic attack when they start dividing, so while they are dormant they survive antibiotic treatments. Short courses of high dose antibiotics kill off large numbers of dividing bacteria but can’t reach dormant ones.  

Here the bacilli are entering the epithelial cells.

Changes to the tissue lining of the bladder

4. The bladder becomes inflamed

The cells that have become colonised by the infection causing bacteria – in this case bacilli – send distress signals to the immune system, which causes an inflammatory response.

Blood vessels dilate up and cause the bladder wall to look red or inflamed. Some of these blood vessels might burst and leak blood into the urine which will be detected on dipstick analysis or microscopy.

Attracted by chemicals, called cytokines which are released by the infected cells, bacteria start to infiltrate the urothelium (the tissue lining of the bladder and parts of the urethra).

The white blood cells fail to detect a problem because the bacteria are hiding inside the epithelial cells. But the urothelial cells do detect a problem and this standoff results in chronic inflammation and pain.

This inflammation and pain can persist despite apparently ‘normal’ urine results. This is because standard tests look in the wrong place. The bacilli are safe, lying dormant inside the urothelial cells and not in the urine which is collected for tests.

Here you can see the bacilli inside the epithelial cells and the white blood cells, shown in red, starting to arrive.

The bladder becomes inflamed

5. Persisting inflammation causes the urothelium to thicken

All epithelial tissue thickens when stressed in any way through a process called metaplasia (think of the skin on your feet).

The tissue lining of the bladder and parts of the thickens as it attempts to form a protective barrier. But it is not very effective – the microbes are already inside the cells.

Both inflammation and the increased number of urothelial cells thicken the wall of the epithelial tissue.

This thickening causes some obstruction which leads to the most sensitive symptom of infection – voiding. Voiding symptoms include hesitancy to pee, a reduced stream, intermittency – stopping and starting, terminal dribbling, post dribbling and double voiding – feeling like you need to go back pee again straight after going.

The thickened and inflamed bladder wall reduces bladder capacity. Inflammatory chemicals can cause the bladder muscle to contract inappropriately.  Both cause symptoms like needing to go more frequently, more urgently or urge incontinence – a sudden and strong urge to go.

Here you can see the bladder wall thickened and inflamed.

Persisting inflammation causes the urothelium to thicken

6. Bacteria that cause disease develop in the biofilm

Biofilms – groups of microbes which come together in a jelly and stick to the inside or outside of cells – are a normal part of our body. They are found all over our body.

But when bacteria that can cause infection and disease get into a biofilm, these bacteria stop dividing and become unsusceptible to antibiotic attack. The now dormant pathogenic bacteria irritate the cells and cause inflammation.

From time to time the pathogenic bacteria can wake up, divide vigorously, burst out the cell and set up fresh infection in new cells.

The white cell count is the best marker of urinary infection but it needs to be done straight away on a fresh, unspun, unstained specimen of urine examined using a microscope and a haemocytometer counting chamber.

Here you can see white cells, shown in purple, in the urine.  The urinary red blood cells which sometimes accompany inflammation of the bladder are shown in red. The microbes, shown in green, can be seen forming biofilms on the surface of cells and inside the cells.

Bacteria that cause disease get into biofilm

7. Cells are infected

Pathogenic bacteria escape from shed cells, divide and infect new, fresh cells at the base of the bladder lining.

The body’s natural immune system responds to the infection by shedding the cells. It’s the most effective way of getting rid of the infection.

But the bacteria have detected that they are inside a cell that is dying. They must escape, by waking up and dividing vigorously to create a microbial swarm that bursts out of the cell into the urine.

Continued division causes a ‘planktonic flare’ which can lead to an acute cystitis attack.

Here the bacilli bacteria have woken up and are bursting out of the cells into the urine. Healthy cells at the base of the urothelium are colonised by the bad bacteria. The infection spreads.

Cells are infected

8. Persister microbes dormant in the cells of the bladder wall are one feature of a chronic infection

On the left a single microbe is dormant inside a cell – we call this a persister microbe. The microbe wakes up and start dividing – this is shown in stages as you move to the right. As the cell fills with dividing microbes it becomes damaged and the dividing microbes leak out into the tissue spaces in the bladder wall. This causes an acute flare.

Eventually the cell dies and the microbes continue to divide through the tissue spaces. If they are given the chance they will set up new, dormant, persisters inside fresh cells.

When the microbes are dividing, they are particularly susceptible to antibiotic attack. During a flare short courses of antibiotics can make immediate improvements only for symptoms to return in a few weeks. A short course of antibiotics doesn’t tackle the root of the problem – the existence of dormant persister microbes that are waiting for the right moment to break out of the cells again.

cells dormant in cell walls wake up and spread infection

9. An chronic infection in action

These images bring a chronic infection to life. To see this in a lab clinicians use special stains and different light filters to make sense of the complexity happening inside your cells, bladder wall and microbiome.

 

a chronic UTI in action - illustration of what it looks like under a microscope

These images have been drawn based on recent experiments in laboratories at University College London using human bladder cells, living culture of a human urothelium, and mouse models of chronic cystitis.

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