Sickness behavior may be a coordinated whole organism immune strategy

Symptoms such as fatigue, loss of appetite, altered sleep, and social withdrawal are often treated as inconvenient side effects of infection. While some scientists have suggested that they may serve a protective function, it is widely assumed that they're byproducts of being sick.

Now, in a new perspective published in Trends in Immunology on April 30, Whitehead Institute Member Zuri Sullivan and colleagues propose a different way of thinking: what if these behaviors are part of an integrated immune strategy that operates across scales - from individual cells to tissues and organs, to the whole organism - and helps promote survival?

Sullivan studies "sickness behavior" to understand how the immune system communicates with the brain to produce these changes during illness - and what they can reveal about how the body coordinates its defense. This work points to a broader biological question: how living systems, from single cells to whole organisms, detect and respond to threats.

We sat down with Sullivan to learn more about how the brain interprets immune signals, how these responses may help organisms fight infection, and what they could reveal about disease and immunity. This interview has been edited for length and clarity.

That work shifted how I thought about immunity, from a local defense system to something broader: a whole-body program that helps shape how we interact with the environment in ways that support survival, including avoiding foods that are harmful or allergenic.

That idea stayed with me in my postdoctoral work in neuroscience, where I studied sickness behavior - things like reduced appetite and social withdrawal during infection. I was interested in how inflammation affects behavior, especially through the hypothalamus, a brain region that controls many of the body's responses during illness.

The brain–immune axis is one of the ways the body senses and responds to what's happening in the outside world. The nervous system does this through our senses, while the immune system uses molecular sensors to detect pathogens and other signs of danger.

The two-way communication between these systems helps coordinate how the body responds to threats. We see this most clearly during infection, in what's called sickness behavior - things like loss of appetite, fatigue, or social withdrawal. But this connection also matters beyond infection, including in conditions like long COVID and the effects of chronic inflammation on the brain.

In our work, we try to construct a bigger picture of how the body protects itself. Individual cells can defend themselves, tissues like the gut can mount local immune responses, and the brain–immune axis represents the highest level of this system, where the immune system and the brain coordinate to affect both physiology and behavior across the whole body as part of a unified defense response.

WI: Is the brain–immune axis disrupted in chronic diseases like long COVID or other neuropsychiatric disorders?

ZS: In some conditions, the immune response that is normally helpful can become dysregulated. This can happen after infections or due to genetic and environmental factors. When that happens, it can lead to chronic inflammation that starts to damage tissues-for example, scarring in the lungs after infection, or conditions in the gut like inflammatory bowel disease (IBD) or irritable bowel syndrome (IBS).

There are still two main possibilities being studied for long COVID. One is that a small amount of virus remains in the body and keeps the immune system activated. The other is that the virus is gone, but the brain–immune axis becomes dysregulated and keeps the immune system in an activated state. Researchers are still working to distinguish between these two.

What's also striking is that there are strong associations between inflammation and both neurodevelopmental and neuropsychiatric disorders. For example, people with autism have higher rates of inflammatory gut conditions like IBD and IBS, and many also experience gastrointestinal symptoms. People with IBD and IBS are associated with being at a higher risk of developing anxiety and depression, especially during a flare-up.

What this suggests is that brain–immune communication can influence both brain function and body function in both directions. The challenge now is figuring out causality - whether inflammation drives changes in the brain, the brain drives inflammation, or if it's a feedback loop between the two.

WI: How can your proposed framework inform how we think about treating infections in the clinic?

ZS: I think it can inform treatment in a few ways. Right now, when people get sick, we often focus on treating symptoms: reducing fever with medications like Tylenol, overriding behaviors like reduced appetite by providing nutrition through feeding tubes in critically-ill patients. But if sickness behavior is part of an organized response, then it becomes important to understand what these behaviors are actually doing before deciding when to suppress them and when to support them.

The hope is that this kind of framework would eventually help us interpret complex symptoms during and post-infection in humans and have more targeted ways to treat them.

Source:

Whitehead Institute for Biomedical Research

Journal reference:

https://www.cell.com/trends/immunology/fulltext/S1471-4906(26)00076-1