Fish run fevers to fight infection

A common consequence of infection is fever; at least for warm-blooded creatures like us. In response to various inflammatory signals, the brain's hypothalamus turns up the thermostat and our temperature climbs with inevitable consequences. We, in response, reach for the packet of paracetamol and bring it down again. But are we, by doing that, prolonging our illness? The fact that so many animals have this same fever response to infection argues that it must serve a beneficial purpose. But studying it is very difficult, because if we artificially alter a warm-bloodied animal's body temperature, the metabolic stress we inflict clouds our ability to ask questions about the impact on the infection. So the genius solution that the University of Alberta's Daniel Barreda hit upon was to work with a cold-bloodied species, because, yes, fish run a fever when they're infected too, but not by boosting their metabolic rate: by moving to warmer patches of water to force up their temperature. And this means they're perfect for studying the impact of fever on immune function, as he explains to Chris Smith…

Daniel - The beautiful thing about this fish is that it's very comfortable in temperatures between 1.4 degrees and 34 degrees. Goldfish, like other cold blooded vertebrates, do not have the capacity like we do to change body temperature through metabolic means. So instead they actually move to a warmer or colder temperature. So fish will go to a warm side of the pond and be able to induce or stimulate that fever through behaviour rather than through metabolic means.

Chris - You are telling me that goldfish run a temperature when they get sick like we do?

Daniel - They do! So if you look at the pathways that are involved, they are shared. Yes, there are physiological differences and we expect that there's going to be some differences between the febrile responses, but for now they're largely shared and the trigger is just behaviour when you're cold-blooded versus metabolic when you are warm-blooded.

Chris - So what did you do to these fish then to make them do this so you could investigate it?

Daniel - Well, that was the most beautiful thing I think, out of this study. The fact that we were able to stimulate them with a pathogen or with a vaccine, and we simply observed them. So it's not that we really manipulate anything in the animal themselves. What we did have to do was create an environment where they would be able to actually show what that natural behaviour was, and that was the most challenging thing.

Chris - What do you mean a tank that's got hotspots and cold spots?

Daniel - Exactly. So this was one of the fanciest tanks that you'll ever see to hold a fish. Essentially we had a tank that had zero physical barriers, but there were multiple different temperatures within this tank. So everything was controlled through fluid dynamics. We had over five or six engineers working on this for a couple of years and basically got it to the point where we have a very discreet gradient, so different temperatures that were very consistent for over two weeks, and we were able to just simply put the fish there after they were challenged, after they were vaccinated. And look at what happened.

Chris - And what does happen?

Daniel - When the fish encounter a pathogen, they will move to the warm side of the tank. And what was really interesting to us is now that we had that extra resolution to observe this, was that they do so very dynamically and they will go to the warm side of the pond and then they'll stay there for the duration of their fever and they'll come back.

Chris - If you can control the temperature in that way, you can presumably do experiments where you infect or challenge a fish and then you deprive it of access to such a high temperature and it has to, therefore it can still choose to go somewhere warmer, but it might not be as warm. What happens if you do that?

Daniel - Well, in our case, we were able to have what we call a control group that allowed us to see exactly that. And when the fish were challenged, so they they encountered a pathogen but the tank was held at a specific temperature, in this case, the base temperature that they had been acclimated to, they did not get all the benefits that we found with the tank with all the temperatures. So we didn't see their capacity to clear the pathogen being as fast. They weren't as good at controlling inflammation and they weren't as good at repairing the tissue that had been damaged by this infection.

Chris - Some bacteria, though, grow better at higher temperatures. So is it still beneficial to the fish to go to that higher temperature or is there a middle ground and do they know what that middle ground is?

Daniel - That is an excellent question and that was one of the concerns going in. Fever is typically thought about as moving pathogens away from the temperature that they prefer, but yet we understand that many of these pathogens do better at the warmer temperatures. In our case, the aeromonas bacteria that we used grew better at the higher temperatures, yet the fish were much better equipped to combat this pathogen when they got the chance to move to this warmer temperatures,

Chris - Did you look inside the fish to see what effect the higher temperature was having on their immune system and on their physiology to effect this improved recovery at higher temperature?

Daniel - Yeah, absolutely. We looked at the capacity of the white blood cells to come to the site of infection and that was much more efficient. And what was interesting is it wasn't more white blood cells coming to the site, it was just they were coming earlier. And you can imagine if white blood cells come earlier, they find less pathogens at the site because the pathogens have had less chance to grow, so therefore it becomes a much better scenario that is in a favour of the host.

Chris - Do we know how the white blood cells improve their efficiency at these high temperatures? What the mechanism of that is?

Daniel - What we found was that at the site of infection, there was earlier production of various molecules that call on those white blood cells. The other thing that we saw was there was much better engagement of the central nervous system and that is actually able to create what we call a systemic response. So basically a whole body response, to better equip this animal to be able to combat this infection.

Chris - And you think that the same thing is almost certainly going on in us when we run a fever. We've got the same molecules, the same cell behaviour, and therefore the same gains through running a temperature to fight infection just like these fish are?

Daniel - Well, we've been studying comparative systems, so basically different types of animals for many years. And what we find is there's a lot of shared responses, particularly in what we call the innate arm, which are those very well conserved early responses from the immune system. And the second aspect is that there's well-documented survival advantage, not just in fish and other cold blooded vertebrates, but also mammals. Rabbits infected with renderpest, for example, survive much better if you allow them to have that fever response. And there's many other examples in the literature.

Chris - The strange thing though is that because we feel so awful when we run a fever, we end up popping pills like paracetamol to bring our temperature down. Are we therefore making ourselves potentially suffer less but for longer by doing that? Should we just grin and bear it and run a fever then?

Daniel - I think there's a few factors to consider. We do think of fever as a symptom and, and I think that has to change. The second aspect that is also very important is not just taking the antipyretics at the time of, but there's many people in the general public that may take this preemptively, whether it is before a kid goes up for vaccination and you simply do not want him to get cranky after, or if you are a sports person, you may think that, you know, you don't have very good ankles and you, you take one of these drugs right before a game just simply to prevent that inflammation from happening. Yes, you may be alleviating some of the symptoms, but the question is are you losing something? Of course we have to confirm this in mammals, but based on everything that we've been able to observe, it seems that at least a good part of it will be shared.