Falling ill with a virus is a pretty reasonable excuse for being unhappy. Completing day-to-day tasks becomes a burden when you’re feverish and coughing or dealing with muscle weakness and lethargy. It may seem like these pains cause our bad mood when we’re sick, but researchers have known for a long time that viral infections can cause physical changes that lead directly to moodiness and poor mental performance. Now, a team from the University of Freiburg in Germany has pinpointed the underlying mechanisms for how viruses and the body’s antiviral response put us down in the dumps.

Research has suggested viruses cause mood and cognitive changes including sleeplessness, headache, and depressive-like behavior. Even the body’s response to being infected — the release of antiviral molecules called type I interferons — can contribute to irritability, insomnia, and cognitive changes. This leads to unpleasant side effects when these interferons are used in therapy for diseases such as cancer and hepatitis C.

“Cognitive dysfunction occurs frequently in RNA virus-infected individuals, as well as after treatment with type I interferons for autoimmune disorders and certain types of cancer, yet the underlying signaling pathways and cell types involved were not known until now,” said first author Thomas Blank in a statement.

To get their results, Blank and colleague Marco Prinz infected mice with a vesicular stomach virus capable of causing flu-like symptoms in humans. They saw that the viral infection caused an increase in the duration of animals’ immobility response while swimming — a sign of despair. After testing to be certain that it was the sickness that caused this reaction, the researchers looked into the mechanism behind it.

The authors believe that the cells lining blood vessels in the brain communicate with both the immune system and central nervous systems, acting as translators for incoming signals from the periphery to the brain. After the body is infected, type I interferons increase, causing those cells to produce a protein called CXCL10, which in turn slows the  neuronal functioning in the hippocampus. That brain region is significant in learning, memory, and mood. Blank said this “established a potential target for the treatment of behavioral changes during virus infection or type I interferon therapy.”

Armed with this knowledge, researchers could develop new interferon treatments with fewer side effects.

“In future studies, we will further explore the molecular and cellular changes underlying viral sickness behavior,” Blank said. “In the meantime, our findings suggest that preventing the release of CXCL10 or blocking its receptors at an early phase should eliminate at least the initial stages of sickness behavior seen in response to viral infection of type I interferon therapy.”

Source: Blank T, Detje C, Spieb A, Hagemeyer N, Brendecke S, Wolfart J. Brain Endothelial-and Epithelial-Specific Interferon Receptor Chain 1 Drives Virus-Induced Sickness Behavior and Cognitive Impairment. Immunity. 2016.