New Study Finds Brain Prepares Immune System Before Infection

A study published in nature reveals the brain activates the immune system before physical contact with pathogens, hinting at new medical applications.

Your Brain Detects Sickness Before You’re Exposed

Our bodies are surprisingly adept at anticipating threats, gearing up for a ‘fight-or-flight’ response even before danger is physically present. Now, a remarkable new study published on 28 July 2025 in Nature Neuroscience suggests that merely seeing someone who looks sick can trigger a proactive immune response. This research, led by Sara Trabanelli, Michel Akselrod, and their colleagues, including senior authors Camilla Jandus and Andrea Serino, delves into how anticipatory neural responses might sense potential infections and prime our immune system.

Traditionally, immune responses are understood to occur once a pathogen has made physical contact with the body. However, this study challenges that notion, providing the first evidence of mutual interaction between our ‘behavioral immune system‘ and our biological immune system, enabling a concerted response before any physical encounter with a pathogen. The behavioral immune system, for instance, drives social distancing in the face of perceived threats.

To explore this, researchers used virtual reality (VR) to expose healthy participants to human-like avatars. Some avatars displayed clear signs of sickness (infectious avatars), while control groups saw neutral or fearful avatars. A fourth group received a flu vaccine to provide a benchmark for a real-life immune activation. Various methods were employed, including psychophysics, electroencephalography (EEG), functional magnetic resonance imaging (fMRI), mass spectrometry, and flow cytometry, to measure behavioral, neural, and immune reactions.

Credit: Nature Publication

a. VR Setup:
Participants first interacted with a neutral avatar to establish a baseline. Then, they were split into three groups. Each group saw one of the following in a second VR session:

another neutral avatar
an infectious-looking avatar
or a fearful avatar

b. Personal Space (PPS) Task:
Participants were asked to respond when they felt a light touch on their face. Sometimes, this happened with no avatar present (called unisensory), and other times while an avatar was moving toward them (multisensory).
The touch occurred at five different time points, corresponding to five distances of the avatar — from far (D5) to near (D1).

c. PPS Reactions Across Groups:
Researchers compared reaction times (RTs) when avatars approached (multisensory) to when no avatar was present (unisensory). Faster reactions at certain distances showed how sensitive each participant’s personal space was. The shaded areas in the graph show where these differences were statistically significant (P < 0.05). Each group had 15 participants. Data are shown as averages with standard error bars.

d–h. EEG Brain Activity:
Brain responses were recorded using EEG at the top of the head (Cz electrode) from 16 participants per group. Black lines on the EEG charts show time periods where the brain activity was significantly different.

d. Compared brain activity from just touch (T) vs. touch plus visual input (VT) to measure multisensory processing.
e. Looked at how brain responses changed based on how close the avatar was (near vs. far), especially during multisensory events.
f. In the infection group, clear differences in brain activity were found when comparing near vs. far infectious avatars.
g. No such differences were found in the control group that saw two neutral avatars.
h. Again in the infection group, significant brain differences were observed even when comparing infectious vs. neutral avatars at a far distance, showing that the brain detects infection risk early.

Neural Anticipation in Action: The study found that our peripersonal space (PPS) system — a network of fronto-parietal neurons that integrates tactile stimuli on the body with external sensory information close to it — is crucial. When infectious avatars approached participants in VR and entered their personal space, participants reacted faster to their face being touched. This indicated a heightened state of alert and a specific PPS effect extending to farther distances for infectious avatars, suggesting the PPS system anticipates potential contact with virtual pathogenic threats even when they are still far from the body. This wasn’t just a general threat response; it was specific to infection cues.

EEG results showed early detection by multisensory-motor areas, with significant neural differences for infectious avatars emerging between 129 and 150 milliseconds, even at a distance. Further fMRI analysis localised these responses to brain regions including the intraparietal sulcus, right primary somatosensory cortex (S1), right anterior insula (aINS), bilateral premotor cortex, bilateral anterior cingulate cortex (ACC), and bilateral middle frontal gyrus (MFG), particularly for far-approaching infectious avatars. These areas are part of the salience network, which is responsible for detecting and filtering important stimuli, including threats.

The Immune System Responds: Most strikingly, blood tests revealed that participants exposed to infectious avatars showed increased activity and changes in the frequency of innate lymphoid cells (ILCs). These cells are considered “first responders” of the immune system. The pattern of ILC activation observed in response to the virtual infection threats was remarkably similar to the immune response triggered by a real flu vaccine. Specifically, virtual and real infections induced a decrease in ILC1s and an increase in ILC2s and ILC precursors (ILCPs), with heightened ILC1 activation suggesting their migration to tissues for early antiviral responses. Natural killer (NK) cells, another type of white blood cell, did not show similar changes.

A Complex Neuro-Immune Cross-Talk: The study also elucidated how the brain might communicate with the immune system. Dynamic causal modelling (DCM) revealed modulated hypothalamic connectivity, specifically when infectious avatars were presented in the far space. The hypothalamus, a key regulator of innate immune responses, showed increased connectivity with the anterior insula (aINS), middle frontal gyrus (MFG), and medial prefrontal cortex (mPFC), while some connections decreased. This suggests the salience network, via the PPS system, influences the hypothalamus, which then links to the hypothalamic-pituitary-adrenal (HPA) axis — a major stress response system.

Further, the researchers quantified neuro-immune mediators like HPA-related hormones, eicosanoids, and neuroinflammatory factors in participants’ serum. A machine learning-based neural network model successfully predicted ILC activation based on a complex, non-linear combination of these mediators, explaining 71% of the variance. The strongest immune response was predicted in a “hot spot” characterised by high HPA-related hormones, low neuroinflammatory factors, and intermediate eicosanoid levels. All three types of signalling factors were found to be essential for driving the immune response.

Implications and Future Directions: These findings demonstrate an integrated neuro-immune reaction to infection threats that occurs not only upon physical contact but also when a potential threat breaches the functional boundary of our personal space. This aligns with the “smoke detector principle,” where biological systems minimise false-negative responses by being exquisitely sensitive to superficial cues of pathogen infections.

While this study is exploratory due to the novelty of the research, the discovery holds significant potential. Andrea Serino suggests future applications could include improving vaccine responses or boosting the efficacy of certain drugs by modulating the immune system through virtual reality. However, further research is needed to fully understand these complex interactions, including how long these effects persist and whether the findings generalise to different age groups or ethnicities. The immune system is incredibly complex, and more detailed analyses are anticipated to build on this foundational work.