In a virtual reality experiment, participants who were approached by human avatar faces with rashes, mounted an immune response in anticipation of an infection.

An encounter with a speeding car, a walk across an icy road, or exposure to germs: daily life comes with experiences that can potentially harm a person. Anticipating such threats and preparing for them is essential to survival.¹ Animals, including humans, routinely modify their behavior to protect themselves from dangers. For instance, people often practice social distancing from individuals who show clear signs of being contagious.

Despite these efforts, microbes often successfully barrel through the body’s defenses, activating an immune response geared towards eliminating them. Scientists know a ton about what happens once pathogens set up camp within the body.² However, how anticipatory behavior equips the body for possible infections remains unclear.

In a new study published today in Nature Neuroscience, researchers showed that the brain identifies the presence of possible infectious agents in the vicinity—even in virtual reality (VR)—and activates early players of the immune system, priming it for a response.³ The study highlighted the potential of VR cues to further explore the intricate link between the nervous and the immune system.

To understand the relationship between behavioral and immune preparedness, Andrea Serino, a neuroscientist at the University of Lausanne, Camilla Jandus, an immunologist at the University of Geneva, and their team recruited 248 healthy volunteers. The researchers designed a VR experiment where human avatar faces with different characteristics stereoscopically entered the peripersonal space surrounding the participants at varying distances. The avatar faces were either neutral, fearful, or showed signs of infection like rashes or coughing. To analyze how the volunteers perceived these faces, the team paired the VR stimuli with a touch to their faces. The participants reacted more strongly to the infectious avatars, as compared to the neutral or fearful ones, even at farther distances, indicating that they anticipated potential threats.

Where is the threat detected in the brain? To answer this, Serino, Jandus, and their colleagues paired the VR experiment with electroencephalography and functional magnetic resonance imaging (fMRI). Since the brain can identify diverse stimuli as threats, the team first attempted to tease apart how it differentiates infections from other dangers. Upon comparing brain activity to fearful and infectious avatars, they observed increased responses in the neural circuits of the fronto-parieto-occipital regions for both stimuli. This was consistent with previous experiments in primates, where researchers had observed that prediction of potential contact with harmful stimuli is encoded in these networks.

To specifically pinpoint the circuits anticipating infections at a higher resolution, the team imaged the brains of the volunteers using fMRI. The ‘salience network’—regions that detect and filter threats—lit up in individuals who saw infectious avatars paired with a touch to their face. Scientists previously observed the activation of some of these areas during vaccine-induced inflammatory conditions. The team dove deeper with a neural network model and observed that potential infectious stimuli activated the hypothalamic-pituitary-adrenal axis, a complex web of interactions that regulates the body’s stress response.

Next, Serino and Jandus investigated if these brain responses translated to immune activation. They recruited a new cohort of individuals and measured their immune cell levels after showing neutral avatars in the VR setup as a baseline. Next, they divided the group into three and displayed either neutral, fearful, or infectious faces to each subgroup. To compare this to an actual immune response, the researchers invited a fourth group of volunteers who received a shot of the influenza vaccine. To the team’s surprise, stimulation with both virtual threat and real infection activated early players of the immune system—innate lymphoid cells and natural killer cells—in the individuals. They likened this to the smoke detector principle in biology, which states that the body often errs on the side of caution, even if it leads to false positives sometimes.⁴

These findings demonstrate that potential infectious threats, even in virtual reality, prepare the immune system for what might come. However, the authors noted that the use of only one vaccine and the focus on exclusively young individuals limit the generalizability of their results, warranting further investigations.