TRPV1–STAT3 signaling as a driver of lethal pathology during pneumococcal nose-to-brain invasion

ABSTRACT Nose-to-brain infection represents a non-hematogenous route by which pathogens invade the central nervous system via neural pathways. The olfactory and trigeminal systems are implicated in this process, but the molecular mechanisms underlying lethal pathology remain incompletely understood. We hypothesized that trigeminal TRPV1 and downstream STAT3 signaling contribute to disease progression during pneumococcal nose-to-brain infection. A murine intranasal infection model using Streptococcus pneumoniae was established with methimazole-induced olfactory epithelial damage and/or resiniferatoxin-mediated trigeminal TRPV1 ablation. We assessed bacterial burden and survival. Spatial transcriptomic analysis of coronal head sections containing the nasal cavity and olfactory bulb was performed to identify region-specific transcriptional responses. Olfactory epithelial damage significantly increased pneumococcal invasion into the olfactory bulb, but ablation of trigeminal TRPV1 improved survival. Spatial transcriptomic analysis identified a distinct transcriptional cluster enriched in methimazole-treated mice that was localized to the olfactory epithelium and adjacent olfactory bulb. The cluster exhibited a STAT3-centered transcriptional regulatory network and enrichment of inflammatory and tissue remodeling pathways. These features suggest the formation of a localized inflammatory niche associated with olfactory epithelial damage. Olfactory epithelial damage and trigeminal TRPV1 activation were suggested to exacerbate nose-to-brain infection cooperatively through STAT3-mediated inflammatory signaling. This TRPV1-STAT3 axis could be a key mechanism linking sensory neuronal activation to lethal neuroinflammation. Targeting this pathway could provide a novel therapeutic strategy for preventing severe central nervous system complications associated with respiratory infections. IMPORTANCE Pneumococcal infection can spread from the nasal cavity to the brain via neural pathways, leading to severe and often fatal disease. However, the mechanisms that drive disease severity have been poorly understood. Using a mouse model, we show that damage to the olfactory epithelium establishes a local inflammatory niche, while activation of the trigeminal nerve amplifies deleterious immune responses. We identify a key signaling pathway that links sensory nerve activation to excessive inflammation in the brain. These findings suggest that targeting host responses, rather than the bacteria alone, may mitigate severe complications of pneumococcal infection. This study provides new insight into the contribution of sensory systems to infection outcomes and highlights potential strategies for therapeutic intervention.