When Nerves Save You From Flu: The Vagus Nerve Keeps the Immune System in the “Green Zone”

A team from Harvard Medical School has shown that sensory neurons of the vagus nerve carrying the TRPV1 receptor (the very same "sensors" of pain/heat/irritants) help to survive the flu infection - not by suppressing the virus, but by managing the immune response in the lungs. When these neurons were missing from mice (they were removed systemically or locally in the branches of the vagus), survival after infection with the influenza A virus dropped, and an inflammatory storm flared up in the lungs: more tissue damage, more pro-inflammatory cytokines, more neutrophils and monocytic macrophages, and at the same time - the interferon antiviral pathway worked worse. Characteristically, the overall "viral load" did not differ, but the virus spread more widely across the lobes of the lungs - with the neural "brake system" turned off, the immune landscape became dysfunctional. When the researchers used antibodies to clean up the aggressive myeloid cells under these conditions, the animals' survival improved significantly, highlighting the key role of TRPV1 neurons in preventing pathogenic myeloid conditions, the main culprits of influenza-related mortality in this model.

Background of the study

Influenza remains one of the most "costly" respiratory infections: a severe course is often determined not so much by the viral load as by immunopathology - dysfunction of the innate response, excessive influx and activation of myeloid cells (neutrophils, monocytic macrophages), which damage lung tissue. Against this background, the question is: who and how "slows down" excessive inflammation, allowing the immune system to hit the virus, but not its own alveoli?

One of the contenders for the role of such a regulator is the vagus nerve. Its sensory (afferent) fibers, including TRPV1-positive nociceptors, sensing heat, irritants and "damage", trigger reflexes (cough, bronchoconstriction) and simultaneously send signals to the brainstem, affecting inflammation in the organs. In recent years, the "neuro-immune" theme in the lungs has been rapidly developing: it has been shown that sensory pathways are able to "read" a viral infection and change the systemic reactions of the disease. But there remained a gap: do vagal TRPV1 neurons help to survive viral pneumonia - or, on the contrary, interfere with antiviral protection?

A recent paper in Science Immunology answers this very question. Using a mouse model of influenza A, the authors selectively switched off TRPV1 neurons (systemically and specifically in the vagus branches) and showed that without them, survival drops, inflammation “overheats,” and the myeloid pool shifts toward pathogenic conditions — while the overall viral load is no higher, but the virus is “smeared” more widely across the lung lobes. At the same time, the interferon response of myeloid cells weakens. The key “causality test”: myeloid cells were partially depleted with antibodies — and with nociceptors switched off, survival increased significantly. This is a direct indication of the role of vagal TRPV1 afferents as regulators of myeloid dynamics and “guards” against immunopathology.

The practical conclusion is still cautious, but important: neural circuits are another lever against severe flu. Theoretically, modulation of the vagus (or its mediators) could “tweak” the myeloid response, leaving antiviral cascades operational. However, the context is critical: the same sensory pathway can behave differently in viral and bacterial processes, and transferring the results to humans will require step-by-step preclinical and clinical trials.

Why is this important and how is it different from the usual picture of “virus ↔ immunity”

The work moves the conversation about flu to the plane of the neuro-immune cross: nerves are not passive observers, but active regulators of how the immune system “fights” the virus and how much collateral damage is done to the body’s own tissues. In the context of pandemics (and outbreaks of severe flu), it is the immunopathology, not the virus itself, that often finishes off the patient. The new study emphasizes that in some people, the severe course of the disease can be explained, among other things, by the variability of the vagus nerve and the TRPV1 neurons associated with it. In popular language, this sounds like this: the vagus nerve helps keep inflammation “in the green zone” - powerful enough to control the infection, but not destroying the lungs.

How was this tested?

The scientists infected mice with the influenza A virus and compared the course of the disease in animals with preserved TRPV1 neurons and in those where these cells were switched off either throughout the body or selectively in the vagus. Then came dense "omics" and histology: they mapped immune cells in the lungs, measured cytokines, analyzed the transcriptomics of myeloid cells (including neutrophil subtypes), assessed interferon cascades, viral load, and distribution of the virus across the lung lobes. In a separate series, to test causality, myeloid cells were depleted during infection - and it was in this "nerves are switched off" situation that this returned some of the survival rate. The key moral of the design: nerves → myeloid cells → outcome is not a beautiful correlation, but a functional chain.

Key facts "point by point"

• TRPV1 nociceptors are switched off → survival is lower, lung damage is higher, cytokines “burn brighter”. At the same time, the overall viral load is the same, but the virus spreads more widely inside the lung.
• Immune shift without neuronal brake: neutrophils and monocytic macrophages expand, the interferon response in myeloid cells weakens, the balance of neutrophil subtypes is disturbed.
• Proof by intervention: myeloid cell depletion rescues some animals with nociceptors switched off → key deleterious branch - pathogenic myeloid states.
• Context is crucial. The same group previously showed that in bacterial pneumonia, vagal TRPV1 neurons can dampen defense, while in viral flu, their "inflammation suppression" protects tissue. That is, the neural regulator is one, but the scenarios are different.

What could this mean for medicine?

The idea of “treating with nerves” is no longer science fiction: vagus stimulation is FDA-approved for a number of inflammatory conditions. New work suggests that in viral pneumonias, it might be possible to target the gentle activation of the “nervous brake” – for example, by modulating vagal reflexes or its afferent branches to tame the myeloid imbalance and allow interferon to “breathe.” In parallel, it is worth looking for molecular mediators between the TRPV1 neuron and the myeloid cell: these are potential drug targets that can be activated without systemic immunosuppression. Finally, the results explain the clinical “variegation” of influenza: some have a stronger neuro-immune brake, and they tolerate inflammation more easily; others have a weaker one – and the risk of “post-viral” damage is higher.

Practical implications (what to think about next):

• Application points:
  • noninvasive vagal stimulation as an adjuvant in severe influenza (RCTs needed);
  • search for small molecules/peptides that mimic the signal of TRPV1 afferents for myeloid cells;
  • stratification of patients by neuro-immune biomarkers (neutrophil subtypes, interferon profiles) for targeted therapy.
• Risks and Limits:
  • TRPV1 is a universal pain/heat "sensor"; gross blockade/activation may have side effects;
  • "Nervous brake" is not useful in all infections - the context (virus vs. bacteria, phase of the disease) is critical.

Limitations that are honest

This is a mouse model; the interventions are ablation/depletion, not clinical procedures. The virus is a specific strain of influenza A; the transferability of the findings to other viruses and to humans is still hypothetical. The authors directly admit that how exactly vagal TRPV1 neurons "hold" myeloid cells in place is an open question. Studies are needed on the circuits (afferents/efferents, mediators), the timing of intervention (early vs. late phase), and combinations with antiviral agents.

Context: Why it's "more than just about the flu"

Flu infects millions and kills hundreds of thousands of people worldwide every year; much of the severity is due to a faulty inflammatory response. Understanding how neural circuits tune the immune system provides a universal “lever” – not to hit the virus head-on and turn off the immune system entirely, but to recalibrate it where and when it protects the tissue. This approach – more precise and potentially with fewer side effects – is what emerges from the new work.

Study source: Almanzar N. et al. Vagal TRPV1+ sensory neurons protect against influenza virus infection by regulating lung myeloid cell dynamics. Science Immunology, 2025 Aug 1; 10(110): eads6243. https://doi.org/10.1126/sciimmunol.ads6243