Why do we feel sick?

December 19, 2016

Have you ever wondered why you feel under the weather when you are sick? Sickness includes not only physical symptoms such as muscle pain and cough but it also involves the state of your mind such as foggy head, crankiness, apathy and fatigue, symptoms familiar to anyone who has ever had flu. And now, you might finally get the answer. However, it is not guaranteed that it will make you feel any better at least not in the near future.

In a new study, researchers from the University of Freiburg in Germany studied why we experience what is called sickness behaviour and what molecular mechanisms are behind it. Even though the sickness behaviour is unpleasant experience, the researchers suspect that the symptoms we suffer during bacterial or viral infections might be beneficial for us. One of the working hypothesis being is that the sickness behaviour concentrates all our energy into the fight with pathogens that have invaded our bodies. This makes sense since brain is the biggest consumer of energy.

On the other hand, the sickness behaviour is often seen as an unwanted side effect of the treatment of patients with cancer and autoimmune diseases with interferons. Interferons are immune molecules which are naturally produced by our cells during viral infections but are also used as a therapeutics with many side effects. Sickness behaviour puzzled scientists for a long time because they assumed that immune molecules as well as most pathogens cannot pass through the blood-brain barrier. The blood-brain barrier is a highly selective and protective barrier that separates our central nervous system from the circulating blood and let through only molecules that are crucial for neural function such as water, glucose and amino acids. This poses a problem for delivering therapeutics to the brain since most of them are big molecules which cannot pass the barrier. Even though the scientists have identified several mechanisms that allow immune molecules to cross the barrier, the question of how the immune system and brain communicate has never been fully understood.

In order to answer this question, the researchers infected mice with a mild virus that causes a brief illness and assessed their level depression. To measure this, the rodents were placed in a container of water. Usually, what happens next is that healthy mice are trying to get out of the water but depressed animals soon give up and float in the water. Surprisingly, the virus-infected mice spent almost twice as much time floating than uninfected mice suggesting that they were depressed. Next, the scientist found that mice cells produced a particular type of interferon, interferon β, in response to the virus. This was not surprising since interferons are the main molecules which fight or “interfere” with viral infections. What was not known though was that the receptor for interferon β was present on the brain’s membranes and immune cells close to the brain’s blood vessels. As a result of viral infection, interferon β stimulates these cells which are all part of the blood-brain barrier.

But there was not enough evidence yet to blame the interferon receptors for the sickness behaviour. To confirm their theory, the scientists used mice that lack interferon receptors and challenged them with RNA molecules that induce similar immune responses as viruses. After the challenge, the researchers measured the rodent’s mental abilities and mood in two simple tests. First, they used the same floating test as before and found that after the “infection” normal mice spent significantly more time floating than mice lacking the interferon receptor. This suggests that the animals are more vulnerable to depression if they carry the interferon receptor. Second, they used a learning test, in which mice were repeatedly shown the location of a platform in a tank of water. Surprisingly, the infected mice lacking functional interferon receptor were able to memorize the location of the platform to the same extent as non-infected control mice. However, the performance of infected normal mice declined by about 50 % when compared to non-infected mice suggesting that their cognitive abilities were massively impaired. This might also explain why it is so hard to learn or remember things while we are sick.

But how does the interferon β cause the changes in the brain? In the follow up experiment, the scientists discovered that the blood vessel cells in the brain can produce another molecule called CXCL10 in response to interferon β. Surprisingly, they observed that CXCL10 was able to alter the responses of neurons from hippocampus, a part of the brain that helps form memories, in a way that it would reduce the animals’ capacity to learn.
The findings of this study are exciting because it identifies a new communication pathway between the immune system and the brain. Previous reports already suggested that interferon β receptor is involved in sickness behaviour but this study showed the role of interferon receptor at brain surfaces and revealed the involvement of CXCL10. The follow up question is whether we can find ways how to stop the unwanted sickness behaviour, especially in cancer and autoimmune diseases patients who are receiving interferon treatment.

Original paper: Blank T. et al. Brain Endothelial- and Epithelial-Specific Interferon Receptor Chain 1 Drives Virus-Induced Sickness Behavior and Cognitive Impairment. Immunity. 2016 Apr 19;44(4):901-12. doi: 10.1016/j.immuni.2016.04.005.