How kidneys protect themselves from bacterial infection

Researchers at the University of Cambridge have found that webs of DNA help protect the kidneys from bacteria that cause common urine infections. The webs - which are called neutrophil extracellular traps - NETs for short - are produced by white blood cells called neutrophils which are attracted to the kidneys and then persuaded to spew out their DNA into the urine stream where it acts as a defence against microbes trying to gain a toehold. Andrew Stewart is part of the Cambridge University team that conducted the study, and I went to meet him at Addenbrooke’s hospital…

Andrew - The question we were asking had nothing to do with what this project turned out to be. So we were trying to work out what in urine we could see to diagnose kidney disease, and mysteriously we found there was lots of DNA in people's urine, healthy people.

Chris - Whose DNA?

Andrew - It was the patient's DNA, but in fragments within their urine. There's a phenomenon known where cells can eject their DNA as a defence mechanism. So we speculated that this might have something to do with it.

Chris - So, it's cells from somewhere in the urine producing system basically chucking DNA out into the urine?

Andrew - Yeah, exactly. So in order to work out what cell it is, because all cells contain the same DNA, we looked at the proteins on them, and these proteins suggested it was coming from a white cell, and a very important white cell called a neutrophil that fights bacteria which causes urinary tract infections.

Chris - But you said these are healthy people?

Andrew - They are. So this was really surprising that healthy people seem to be undergoing some sort of chronic defence mechanism. And given this is in the urine, it's logical that maybe urinary tract infection was important here.

Chris - Is this some kind of defence then. They're healthy, they haven't got an infection and this is why?

Andrew - Absolutely. So we then move to look at mice because we can give mice urinary tract infections. So you get a very small catheter and you put it into the mouse's bladder and you put some bacteria in and the mouse gets a urinary tract infection. So when we did this, we then looked for these nets in the urine that we were seeing in healthy humans and we could see the same thing.

Chris - But the mice have got an infection unlike the humans. So can you stop the mice having these nets and see if they're more prone to infection?

Andrew - Absolutely. So there's a drug that isn't used for anything clinically at the moment in the hospital, but it stops these nets from forming. So we gave some mice this drug versus some mice who didn't have the drug and we found that the mice who had the drug were much sicker. So in the absence of these nets, they got an infection that went from their bladders, which is usually mild up into their kidneys, which in humans can be life threatening.

Chris - Where are the white blood cells that are making these defensive nets hanging out then? Have you now gone and profiled through the urinary tract to see where they're starting out from?

Andrew - We don't really know the answer to it, but there's good evidence from the lab that the kidney has chemicals that pull these white cells towards it in normal healthy humans. And this is then probably increased in infections.

Chris - A million questions now running through my mind because as you say, UTI is a big common clinical problem. If these are so good at fending off infection, if we turn them up, can we cut down the rate of infection? And are people who are more prone to infection deficient in these?

Andrew - We actually did look at this question. So we looked at some genetic information and we found that there was an association between the enzyme that we were inhibiting to prevent these nets from forming, and infections, but also autoimmune diseases. And essentially it's a trade off of one versus the other. So if you have increased risk of infection, you can reduce your autoimmune disease and vice versa. So if you turn them up in your genetics, you're probably actually going to get more autoimmune disease and less infection and vice versa.

Chris - When people go to the doctor, usually women, and they say, I've got some symptoms of a urine infection, the first thing we do is we reach for these sticks that you dip in the urine. One of the things we look for is evidence of leukocytes, white blood cells. So are we finding these things and it's a good thing if they're in there, it doesn't mean they've got an infection?

Andrew - That's a really interesting question and we thought the same thing. Well what does this urine dipstick test actually tell us and what does it mean? This test is 70 years old now. So we actually thought, let's have a look at that test and see what it was doing. So we took some neutrophils from blood from a healthy person and did this several times and found that actually, lots of neutrophils did not activate this test. So that's kind of contrary to what we've thought for 70 years. So then we took those neutrophils, the same neutrophils, and triggered them to do the net formation and they activated the test straight away. So this kind of demonstrates that actually what this test that we've been doing and using on millions and millions of people all the time, probably the commonest test we do, after some simple blood test is actually detecting the DNA being ejected by these cells, not the cells themselves.

Chris - It's detecting the defence not the infection it's designed to prevent. So it could be misleading us?

Andrew - Exactly. So some things, some types of infection are good at triggering net formation and some are bad. And there are many reasons why nets may form independent of infection, and therefore this test is actually much more complicated and this is probably why this test is so difficult to interpret in our population.

Chris - So where next then?

Andrew - So I think we've disrupted them and we now need to understand what drives their formation and what doesn't. One interesting characteristic of this cell is it's quite unstable. It likes to do this, but a lot of the cells weren't doing it. So working out what makes them do it, what makes them not do it, how that changes from person to person and whether that changes in disease, I think are really interesting avenues.