The Brain: A Bodyguard against Infection

It’s the most wonderful time of the year! With the twinkling lights, delicious food, and time spent with loved ones, the winter months pack in a lot of cozy joy and cheer.

However, there’s one particular menace threatening to derail the holiday spirit: viral infections. In the northern hemisphere, cold and flu infections run amok during this time, and it can often feel like you’re dodging sickness left and right in an attempt to stay healthy for the festivities.

We all know that the immune system does a lot of the heavy lifting to defend us against our viral foes, but what if there was another unsung hero rallying the troops for battle before you even realize war is on the horizon?

In this blog, we discuss the role of the brain in anticipating infection, priming the immune system, and avoiding the spread of sickness.

Plan of Attack

It’s no secret that there exists a tight interplay between the neural and immune systems in the coordination of the immune response during infection. However, whether the brain can pre-emptively engage the host’s immunity in anticipation of a potential pathogen has until now remained unknown (Irwin and Cole 2011).

So, Trabanelli et al. (2025) set out to address just that.

They employed a clever system using virtual reality (VR) technology to put participants “in contact” with a sick person without any actual possibility of exposure to pathogens. Individuals were first shown a neutral avatar via the VR system, followed by one of three avatars: an infectious avatar that showed clear signs of illness, a neutral avatar (the control), or a fearful avatar, which served as an additional control as a threatening yet nonpathogenic stimulus.

Through the VR system, this avatar would virtually invade the participant’s personal bubble — known scientifically as the peripersonal space (PPS).

A fourth cohort of individuals who received an influenza vaccine and no VR stimulation was also included in the analysis to compare any response to the perceived nearby infection with that of an actual pathogen.

The researchers analyzed the frequency and activation state of natural killer (NK) and innate lymphoid cells (ILCs) in the blood of the participants — innate immune cells on the front lines of infection.

Interestingly, a similar response was observed in both the virtual and actual infection cohorts, with increased frequency and activation of ILCs compared to the neutral and fearful groups. However, NK cell parameters showed no differences among the groups.

Trabanelli et al. then delved deeper into the specifics of this observation by analyzing the frequencies and activation states of the individual subsets making up the ILC group: ILC1s, ILC2s, and ILC precursors (ILCPs).

Again, they found comparable changes in the virtual and real infection groups, with a rise in the frequencies of both ILC2s and ILCPs, and an increase in the activation index but a decrease in the frequency of ILC1s in the blood, consistent with their activation-induced migration to the tissues.

But how exactly is the brain involved in coordinating this preparatory defence mechanism?

The scientists observed changes in the virtual infection group in the connectivity between the hypothalamic-pituitary-adrenal (HPA) axis — a neuroendocrine system that plays a key role in the body’s stress response and the neuroimmune interface — and the neurons associated with the PPS system.

Taken together, these data support the intriguing idea that ILCs react not only to the physical presence of a pathogen in the body but also become poised and ready for action upon the mere perception of an approaching peril as directed by systems of the brain.

Social Sacrifice

Not only does the brain protect its own body from infection, but, once an illness is contracted, it also actively shields those around it from succumbing to the same fate.

I’m sure most of us can relate to the strong desire to stay in bed or on the sofa in a state of inertia all day while suffering from a cold. But did you know that this yearning is an evolutionary tactic implemented by the brain to both conserve energy for the recovery process as well as to prevent spreading the pathogen to others?

Recently, Yang et al. (2025) decided to take a crack at deciphering the mechanism behind this social withdrawal.

They decided to look at the effect of cytokines in mice — small molecules that can travel through the blood and cerebrospinal fluid, thus creating a bridge between the neural and immune systems. The researchers injected the brains of the mice with 21 different cytokines and compared the response of each one with mice injected with lipopolysaccharide (LPS), a component of the bacterial cell wall that stimulates the immune system similarly to infections.

They found that out of all the cytokines they tested, only IL-1β administration induced the social withdrawal observed in LPS-injected mice.

On closer inspection, they found populations of neurons in the dorsal raphe nucleus (DRN) — a region of the brain known to be involved in social behavior — that expressed the IL-1 receptor type 1 (IL-1R1).

When the scientists inhibited the activity of these neurons, the mice treated with IL-1β no longer displayed any social isolation behavior, therefore indicating that social withdrawal in sick mice is mediated by IL-1β signaling via the neurons of the DRN.

Overall, these studies depict a role for the brain in both offense and defense against pathogenic pests.

So, when the coughing and sneezing reach their peak in the winter months, it may be reassuring to know that we have our own personal guardian looking out for us against the threat of sickness!