Nothing seems to work when you’re sick. When I’m down with the flu, for instance, my muscles ache, my eyes are bloodshot and I don’t feel like doing anything. It’s pretty bad, and if you ever wondered who you have to thank, a team of scientists has singled out a prime suspect: a signaling protein called interferon-β.
In all fairness, the body’s response to sickness following a viral or bacterial infection is supposed to be beneficial. It’s the body’s way of saying ‘Hey, I’m gonna take all this energy to fight the bad guys right here. Sit tight!’
What triggers this resource divestment mechanism has eluded researchers, though — until now. Researchers from the University of Freiburg in Germany got some hints from cancer patients who feel sick as a side effect of interferon therapy. Interferon-α encourages cancer cells to send out chemicals that attract immune system cells to them.
That they feel sick after being treated with these immune molecules is puzzling since the blood-brain barrier is supposed to block any signals from the immune system from reaching the brain. So, neuropathologist Marco Prinz and colleagues decided to investigate the sickness behavior at the molecular level in rodents.
They infected mice with a virus, then placed them in a container of water. This is a standard depression test for mice. Typically, a healthy mouse will struggle in the water, but if it’s down with the flu it will give up fast and just float. Just like I would.
Researchers found that the infected mice spent twice as much time floating in the water, which signaled that they indeed felt sick.
Eventually, they discovered that the virus caused the mice to produce interferon-β, which in turn stimulated receptor molecules on the blood-brain barrier membrane. In response to interferon-β, the blood vessel cells that line the blood-brain barrier produced another molecule called CXCL10. This molecule interacts with the hippocampus — the area of the brain where memories form — reducing the mice’s learning capabilities.
To see if they were really on the right track, the researchers genetically modified mice to lack the interferon-β stimulable receptors, then tasked them with tests that measured cognitive ability and mood.
When these were injected with RNA molecules that triggered the same immune response as the virus, the genetically altered mice performed much better than the infected normal mice. The animals that carried the receptor spent more time drifting in the water and performed worse at tasks that involved memorizing the location of a platform in a tank of water. “Their cognitive abilities were massively impaired,” says Thomas Blank, a neuroimmunologist also at the University of Freiburg, and co-author of the study published in Cell.
This sort of research might lead to the development of novel drugs that minimize the symptoms of sickness. For now, though, the University of Freiburg team are focusing on ways to stop sickness behaviour in cancer patients who are receiving interferon treatment.
“In summary, our study provides evidence for the importance of brain endothelial and epithelial cells in the communication between the CNS and the immune system, and demonstrates tissue specific IFNAR1 engagement during sickness behavior. By the identification of the IFN-induced CXCL10/CXCR3 axis, we offer new drug targets for the management of behavioral impairment during virus infection and type I IFN therapy,” the researchers conclude.