Nociceptor neurons shape antiviral immunity.

The nervous and immune systems cooperate to protect the host, yet the contribution of sensory neurons to antiviral immunity remains incompletely defined. Nociceptor neurons do more than relay pain: they detect viral products and inflammatory cues through pattern-recognition receptors (PRRs), including Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs), and respond to mediators such as type I interferons (IFNs), tumor necrosis factor (TNF), and interleukin-1β (IL-1β). Upon activation, these fibres release neuropeptides and neurotransmitters, including calcitonin gene-related peptide (CGRP) and substance P (SP), while sympathetic catecholamines provide a parallel neural input that shapes vascular tone, leukocyte trafficking, and effector programmes across tissues. Viral infection can also engage neuro-glial circuits in sensory ganglia and, in some settings, spread directly to the central nervous system (CNS), as described for lymphocytic choriomeningitis virus (LCMV), herpes simplex virus (HSV), and selected influenza A virus (IAV) strains. Here, we synthesize evidence that nociceptors shape antiviral immunity in a context-dependent manner rather than exerting uniform control. Nav1.8⁺ afferents restrain excessive inflammation while supporting dendritic cell (DC) priming of CD8⁺ T cells during cutaneous HSV-1 infection; vagal TRPV1⁺ neurons, a subset of Nav1.8⁺ nociceptors, promote disease tolerance during influenza by tuning lung myeloid responses; CGRP signaling drives T helper (Th) 1 differentiation during acute LCMV infection; and sympathetic adrenergic inputs deepen CD8⁺ T cell exhaustion during chronic infection. Defining these neuro-immune circuits may reveal therapeutic opportunities, but species differences, circuit heterogeneity, and the pleiotropic effects of shared mediators will need to be resolved before these insights can be translated to human disease.