The worst part of being sick isn’t always the muscle aches and coughing. It’s the foggy head, the crankiness, the apathy, and the fatigue—in short, what researchers call sickness behavior. A new study uncovers a molecular mechanism that explains why we feel so crummy when we’re under the weather.

“It’s a nice study that’s covered a lot of ground,” says neuroimmunologist Colm Cunningham of Trinity College in Dublin who wasn’t connected to the research. “What they’ve found is very plausible.”

Although sickness behavior is unpleasant, researchers think the symptoms we suffer during a viral or bacterial infection are beneficial, enabling us to divert our energy to fighting the pathogens that have invaded our bodies. For cancer patients and people with autoimmune diseases, however, sickness behavior can be an unwanted side effect of treatment with immune molecules known as interferons, which our cells naturally release when we have an infection.

The condition has posed a puzzle for researchers because they assumed the blood-brain barrier, a protective system that excludes most pathogens and immune molecules from the brain, would block signals from the immune system. Although scientists have identified several mechanisms that allow such messages to cross the barrier and influence behavior, the question of how the immune system and brain communicate “has been only  partially answered,” says immunophysiologist Keith Kelley of the University of Illinois, Urbana-Champaign, who wasn’t connected to the new study.

To delve into the mechanisms of sickness behavior, neuropathologist Marco Prinz of the University of Freiburg in Germany and colleagues exposed mice to a virus that causes a brief illness. The researchers gauged the pathogen’s effects by using a standard test for rodent depression in which the animals are placed in a container of water. The rodents usually struggle to get out of the water, but depressed animals give up quickly and float. Mice spent almost twice as much time floating if they were infected with the virus, suggesting that it was altering their behavior.

The researchers found that the virus spurred the mice to produce a type of interferon, interferon-β. In turn, interferon-β stimulated receptor molecules on the brain’s protective membranes and on the cells that line the organ’s blood vessels, which form part of the blood-brain barrier.

To determine whether these receptors spark sickness behavior, Prinz and colleagues compared normal mice with genetically modified animals that lack the receptors. After injecting the mice with RNA molecules that trigger the same immune responses as viruses, the scientists put the rodents through two tests to measure their mental abilities and mood. In the floating test, normal mice spent about 50% more time drifting than did the genetically modified mice, the researchers report online today in Immunity, suggesting the animals are more vulnerable to depression if they carry the receptor. In a test of learning that requires the animals to memorize the location of a platform in a tank of water, the RNA injections didn’t affect the performance of the mice lacking the receptors. But the performance of the normal mice declined by about 50%. “Their cognitive abilities were massively impaired,” says co-author Thomas Blank, a neuroimmunologist also at the University of Freiburg.

Prinz, Blank, and colleagues had pinpointed two parts of a mechanism that relays immune signals across the blood-brain barrier, but they still needed to nail down what molecule caused changes in the brain. They determined that in response to interferon-β, blood vessel cells produce another molecule called CXCL10. The researchers then measured the electrical activity of neurons from the hippocampus, a part of the brain that helps form memories and also shapes our emotions. CXCL10 altered the neurons’ responses in a way that would reduce the animals’ capacity to learn. “We can explain on a cellular and electrophysiological level what is the basis for this [sickness behavior],” Blank says.

The study is important because it identifies a new communication pathway between the immune system and the brain, Kelley says. Cunningham adds that the data are consistent with his group’s study from last year, which implicated the interferon-β receptor in sickness behavior. But now, the researchers have gone significantly further by identifying the interferon receptor's role at brain surfaces and by revealing the involvement of CXCL10.

Neuroimmunologist Robert Dantzer of the University of Texas MD Anderson Cancer Center in Houston is skeptical of the new mechanism, however. “Cytokines produced by immune cells act locally,” he says. They would remain confined to locations in the body where immune cells were fighting the virus and thus would not travel to the brain and trigger sickness behavior.

But the researchers think they are on the right track. A major question now, Blank says, is whether researchers can find ways to stop sickness behavior in patients with cancer or autoimmune diseases who are receiving interferon treatment.