Bugs and bladder infections

Bacterial infections cause millions of deaths around the world every year. But countless more aren't fatal yet cause untold misery and pain. Urinary tract infections, like cystitis. are caused by bacteria getting into the bladder. They're very common - around half of all women are likely to have one at some point in their life - and as well as causing pain and discomfort, recurring or chronic infections can also lead to incontinence, especially in the elderly. But the reason for these recurring infections sounds more like a horror story than a scientific research paper.

To find out more, Kat Arney spoke to Dr Jenny Rohn at University College London - and the first thing I wanted to know was what happens when bacteria get into the bladder...

Jenny - Well, typically, they get up there and it's a nice, warm, wet environment and they're quite happy, but it's a rather hostile place because, of course, you are voiding your bladder quite regularly. So, if you're a tiny, tiny bacteria, say, you are 2 or 3 microns wide, and you're being faced by somebody peeing, it's like the force of the fire hose. Normally, this is what happens. The bacteria get up there and then you have a pee, and then swish, they're whizzed out and it's not a problem. But bacteria are very, very sticky. They've got special proteins on them that like to stick to cells, and E. coli in particular - which is one of the major causes of UTI - is really, really good at sticking to cells.

OK, so normally, this is what happens. The cells of the bladder, they're sort of there and the bacteria get up there and they manage to evade the peeing process. And they're clinging on there, they're sticking on, and they're causing a little bit of havoc and mayhem. This is when you might actually start feeling some symptoms. You might feel some burning when you pee. You might start peeing very, very frequently and then you might have a look at your pee, and you might notice it's really cloudy, and maybe there's some blood in there, and you know you've got a bad infection.

And then you go to your GP and your GP gives you antibiotics, and you take them for a week. You feel better usually. End of story, right? But actually, it's not the end of the story. You might get it again in a few months and many women suffer with these recurring UTIs. It doesn't make any sense because this women are usually not having bad hygiene. They can't shake this bug.

Kat - So, what's going on there? What's making this certain bacteria just hang around?

Jenny - The key to the mystery was solved about 10 years ago and this observation that bacteria are not always just sticking to the outside. So, a bunch of scientists worked out the bacteria are brewing inside the bladder. So this is very, very strange. E. coli is a free-living organism. It's not a parasite. It's never, never supposed to go inside cells and in fact, the cell never lets stuff go in there that's not supposed to go in. So if you were a cell, you got invaded by a cheeky bacteria, you'd throw up a big cage around it and you degrade it, and get rid of it. This is what happens all the time when cells are molested by various things. They just shut them down. Also, the immune system should be doing this stuff and getting rid of these things.

What happens is when the bacteria get inside the cell, for some reason that we still did not understand, they just escape. They escape all of these controls. They're probably in some sort of bubble, so they've been internalised by the cell and they're in some sort of bubble, and this bubble is supposed to be heading toward the degradation machinery, the stuff that's supposed to break them into little pieces and kill them. But for some reason, they escape from these bubbles. They get out. They have some sort of communication with the molecules around and they manage to slip the net, they sort of breakout of these little prisons. They must be tricking the cells somehow because a cell shouldn't have to do that. So we think there's some sort of weird molecular communication going around that's fooling the cell into thinking that this bacteria are supposed to be there and they're supposed to be released.

So once they're released, it all goes really, really strange. So they start dividing, and they start dividing, and dividing and dividing. It's like a big mass of bacteria inside the cell and they get bigger and bigger, and bigger. Meanwhile, you don't know you're sick. You feel fine. You've got...

Kat - No sign of any of this.

Jenny - No sign of anything, but deep inside your bladder, there's these hidden colonies of bacteria that are growing and growing. And then actually, if you look at them down an electron microscope, you can see they're actually pushing at the cells. If a cell is a like a balloon, it's this huge mass inside that's pushing the cells out, distending it. You can see these big bubbles which are known as pods which you think is great, but...

Kat:: This sounds like some kind of horror fil!

Jenny - Yes, it's so alien because you know what's going to happen next, right?

Kat - Out they go and they all start again.

Jenny - At some point, the pod get so big that cell literally explodes. And these guys just whizz out. There's millions of them, billions of them. They whizz out into the bladder and start all over again.

Kat - What's going on then at a molecular level? Do you have any clues about some of the genes and the proteins that are actually involved in this weirdly subversive process?

Jenny - Hardly anything, I'd say. There's been a few studies done suggesting that there's a protein called actin which is inside all our cells that makes a bit of a skeleton and it keeps the cell a certain shape and everybody's got actin. And there's a thought that maybe in these bladder cells, the actin is supposed to be keeping it in check and it gets somehow subverted, but really, nothing's known. Absolutely, not. That's why I'm so excited about this project because it's completely a wide open field.

Kat - So then, tell me about how you and your lab are trying to approach this question?

Jenny - We've got two basic approaches on our lab. One approach deals with how we're going to treat these people, how can we design better therapies? Because the pods are inside the cells, the antibiotics that you take can't get in there. So, antibiotics, many of them cannot pass through the cell membrane. So, we need to find better ways to get antibiotics inside the cells. And the other thing is just basic cell biology. What happens when the bacteria get inside? What does a cell do? What genes are required to allow these bacteria to escape from these cages? There must be something going on, so we'll be using a genetic approach, whereby we knockout genes that we think might be involved and see whether that stops the bacteria from getting out. So, it's the sort of basic approach where, if you wanted to know how a car works, you could systematically break each part of the car and see what happened. It's the same sort of thing. We're going to systematically interfere with genes that we think might be involved and then see whether that affects the infection process.

Kat - So how many genes are you going to start looking at?

Jenny - Well, there's about 20,000 genes. We've got a collection now of maybe 50 genes that I think might be implicated. They're genes that are expressing proteins that are near the surface of the cell, genes that express proteins that tend to be involved in trafficking of particles to and from the surface. So there are sort of things that are around there anyway, things that will probably be hanging out when these bacteria dive into the cells. And there's a number of leads we have and I think that we should be able to find something. I also want to do some really interesting live imaging where we can make green bacteria and infect cells and see if we can actually see the bacteria going in and what they're doing.

Kat - And then presumably, watch them exploding back out.

Jenny - Yeah, there are - I've seen some amazing movies so I think that is possible. This technology makes it possible and I think it will be quite fun just to watch, but ultimately, with cell biology, you can't learn everything just by looking. Things are so microscopic and complicated that you have to start doing sort of genetic interference to see things.

Kat - What could be the benefit if we could make significant improvements to understanding and treating these UTIs?

Jenny - I think that if we understand how the bacteria get in, how they persist, and we should be able to prevent that from happening in the first place. I mean, you will never be able to prevent cystitis. Women will always get urinary tract infections, but what we will be able to prevent, if we know how it works, we can prevent the sort of invasion and the long term colonisation of this sort of alien pod-like thing. If we can prevent that from happening by targeting it with the drug, that would be brilliant. We see 150 patients a week in the clinic here and these people are really, really miserable and I think that if we can make a difference by studying this bacteria and improving their therapy, it will make a huge difference to their lives.