A new animal model of immunity
The mammalian immune system is notoriously complicated and difficult to unpick. But, speaking with Chris Smith, Kate Buckley from George Washington University has found a much simpler creature with just a hundred or so immune cells that - despite being separated from us by half a billion years of evolution - uses many of the same signals our own human immune system does...
Kate - Sea urchins have what we call a biphasic lifestyle or a two-step lifestyle, sort of like a butterfly and a caterpillar. They go through a larval stage before they turn into an adult. As larvae, these animals which are about twice the width of a human hair, they live for about two months in the ocean and they swim and they feed and they're fully competent organisms but they live in seawater which is really a microbe-rich environment. There’s a million bacteria per millilitre of seawater. And so the question is how are these tiny animals able to deal with this onslaught of microbes?
Chris - Because when a human baby is born, it gets preloaded with the cross-section of its mother’s immune system in the form of antibodies fed to it across the placenta. So, what does a sea urchin do?
Kate - It doesn’t have any real pre-programming developmentally. It just has to rely on what’s in its genome basically. And so, it has a small set of about a hundred immune cells that are able to recognize pathogens and respond. It makes anti-microbial peptides but that’s really all that’s known about it at this point.
Chris - So how did you approach it? What did you do?
Kate - We exposed these larvae to many different species of bacteria and just looked at them under a microscope to see if there were any observable changes in how their cells behaved or how the animals looked. And we found this one species of bacteria that caused what looked a lot like an inflammatory response. So, cells came from the periphery of the organism and travelled to the gut and that’s sort of a classic inflammation response.
Chris - What is the bug? And what’s the signal that is then radiating out through the organism’s body to tell these immune cells, “Come here. We’ve got a problem”?
Kate - The bacterium is called Vibrio diazotrophicus. It’s commensal. It forms long lasting relationships with adult sea urchins. And so, what this means is that the animal probably has developed an evolutionary strategy to say, “Okay, a little bit of this bug is okay but too much of it and we have to call in an immune response.” And the signal is this cytokine called Interleukin 17 or IL17.
Chris - That’s interesting, isn’t it, because Interleukin 17 is a lynchpin of my immune system and yours.
Kate - Right. That’s absolutely right. And so, what we found basically is that these larvae which are just a few thousand cells, the way that they control their gut-associated immune response is very similar to the way the human gut immune response is mediated. So, that it was surprising.
Chris - Are you saying then that because we all originated in a similar way that this interleukin signalling is very, very ancient and that’s why sea urchins have it and why we still have it today, it’s how we tell our immune response what to react to and what to ignore?
Kate - Right. Exactly. So, sea urchins are echinoderms which diverged from the vertebrates about 550 million years ago so this is really a deeply conserved element of the gut response.
Chris - And although the signals may be the same, the effects they have on cells and the way they're interpreted may not. So were the same receptors used then in the sea urchins so their immune cells see this Interleukin 17 family of signals in the same way that my immune cells do or not?
Kate - They do actually. Yeah. And so that’s one of the advantages of this model is that it’s basically a simplified version of the immediate response in the vertebrate gut. And so, the IL17 receptors are expressed in the gut and more widely. And some of the genes that are turned on when the receptors interact with IL17 are known to be associated with IL17 response in humans. And so, what this tells us is that there’s some conservation and the signalling pathways between sea urchins and vertebrates. And this gives us hope that we will be able to find additional things that are also conserved first in the sea urchins and then apply them back to humans.
Chris - Because this whole system is notoriously difficult to understand and unpick because it’s so complicated in big higher organisms and getting to the root of it is absolutely critical if we want to understand how things like the microbiome operate and how it influences our immune maturation, so do you think what you’ve got here then is a much simpler, much more tractable model for how that part of our immune system a. evolved and b. actually works?
Kate - That’s correct. So, the frontline of defence in your gut immune system is a genomically-encoded or what’s called innate immune response. And that’s something that sea urchins and humans have shared. And what we’re able to do with this larva is, since it’s transparent, we can actually just look at the gut. We can watch what the cells are doing and it’s a lot easier than getting at a mouse gut.