Symptoms such as fatigue, loss of appetite, changes in sleep, and social withdrawal are often treated as untoward side effects of the infection. They are widely thought to be a byproduct of disease, although some scientists suggest they may serve a protective function.
Now, with a new perspective, Trends in immunology On April 30, Whitehead Institute member Zuri Sullivan and others proposed a different idea. What if these actions were part of an integrated immune strategy that works across scales, from individual cells to tissues and organs to whole organisms, to help promote survival?
Sullivan studies “sickness behavior” to understand how the immune system communicates with the brain to produce these changes during illness, and what this reveals about how the body adjusts its defenses. This research points to broader biological questions about how living systems, from single cells to entire organisms, detect and respond to threats.
We spoke with Sullivan to learn more about how the brain interprets immune signals, how these responses help organisms fight infection, and what they can reveal about disease and immunity. This interview has been edited for length and clarity.
Whitehead Institute: How did you start thinking about disease behavior as a form of whole-organism immunity?
Zuri Sullivan: During graduate school, I discovered that immune cells in the gut not only protect against pathogens, but also help regulate the body’s response to food by changing the function of intestinal tissue in response to food.
This research changed my way of thinking about immunity from a local defense system to something broader, a systemic program that helps shape how we interact with our environment in ways that support survival, such as avoiding harmful or allergenic foods.
This idea stayed with me in my postdoctoral work in neuroscience, where I studied disease behaviors such as decreased 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.
By combining two research fields, immunology and neuroscience, we have arrived at an integrative view that immunity operates at multiple scales and shapes both body function and behavior as part of a coordinated system.
Whis: We often think of the brain and immune system as separate systems. How are they connected and why is this connection important?
ZS:For a long time, the brain was thought to be largely separate from the immune system and protected by the so-called blood-brain barrier, which tightly controls substances that enter the brain from the bloodstream. Although this barrier remains very important, we now know that the brain is not isolated. The brain and immune system communicate with each other, and that communication can influence both brain activity and behavior. This connection is called the brain-immune axis.
The brain-immune axis is one way the body senses and responds to what’s going on in the outside world. The nervous system does this through the senses, while the immune system uses molecular sensors to detect pathogens and other signs of danger.
Two-way communication between these systems helps coordinate how the body responds to threats. This is most clearly seen in so-called sick behaviors such as anorexia, fatigue, and social withdrawal during infections. But this link is important beyond infectious diseases, including situations such as long-term COVID-19 infections and the effects of chronic inflammation on the brain.
Our research seeks to build a bigger picture of how the body protects itself. Individual cells can protect themselves, tissues such as the intestine can mount local immune responses, and the brain-immune axis represents the highest level of this system, where the immune system and brain work together to influence both systemic physiology and behavior as part of a unified defense response.
WI: In chronic diseases like long-term COVID-19 and other neuropsychiatric diseases, is the brain-immune axis disrupted?
ZS: In some situations, normally helpful immune responses can become dysregulated. This can occur after infection or due to genetic and environmental factors. When that happens, it can lead to chronic inflammation that begins to damage tissues. Examples include scarring of the lungs after infection, and intestinal conditions such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS).
There are still two main possibilities being studied regarding the prolongation of COVID-19. One is that a small amount of the virus remains in the body and keeps the immune system activated. The other is that the virus is gone, but the brain-immune axis is dysregulated and the immune system remains activated. Researchers are still working to differentiate between the two.
Even more surprising is the strong association between inflammation and neurodevelopmental and neuropsychiatric disorders. For example, people with autism have a higher prevalence of inflammatory bowel diseases such as IBD and IBS, and many also experience gastrointestinal symptoms. People with IBD and IBS are associated with a higher risk of developing anxiety and depression, especially during flare-ups.
This suggests that brain-immune communication can bidirectionally influence both brain and body function. The current challenge is to determine the causal relationship: does inflammation cause changes in the brain, does the brain cause inflammation, or is there a feedback loop between the two?
WI: How can your proposed framework inform how we think about treating infectious diseases in the clinic?
ZS: I think it can inform treatment in several ways. Now, when people get sick, we often focus on treating the symptoms, lowering fevers with drugs like Tylenol and controlling behaviors like loss of appetite by feeding critically ill patients through feeding tubes. But when sick behaviors are part of an organizational response, it becomes important to understand what these behaviors actually do before deciding when to suppress them and when to support them.
A useful example can be found in a 2016 mouse study. Researchers found that force-feeding sick mice using feeding tubes produced different results depending on the type of infection. Bacteria-infected mice were more likely to die, while virus-infected mice had improved survival rates. What this suggests is that behavioral changes such as decreased appetite may actually be tailored to the type of immune challenge the body is facing. Therefore, understanding how these behavioral changes affect the course of infection could help reveal which interventions are helpful and which may impede recovery.
In addition to acute infections, it also has an impact on symptoms such as particularly long-term COVID-19 infections and other neuropsychiatric and post-inflammatory diseases. One important possibility is that the immune system plays a causal role in causing or maintaining some of these conditions. If so, it becomes especially important that the immune system is highly “drug-prone.” There are already many treatments that target immune pathways. Therefore, understanding how immune signals influence the brain could open up new ways to intervene in conditions where current treatments don’t respond to patients.
What we need is a better map of how different infections affect the brain over time – what we might call the “neural signatures” of infections. Because animal studies can track both immune responses and brain activity over time, we can begin to build such maps of how brain function and behavior change from health to infection.
It is hoped that this kind of framework will eventually help interpret the complex symptoms during and after human infection and establish more targeted treatment approaches.
sauce:
Whitehead Biomedical Research Institute
Reference magazines:
https://www.cell.com/trends/immunology/fulltext/S1471-4906(26)00076-1
