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However, the regulatory mechanisms that govern the direct nose-to-brain invasion of\n                      <jats:italic toggle=\"yes\">S. pneumoniae<\/jats:italic>\n                      remain unclear. The nasal cavity is innervated by both olfactory and trigeminal nerves, which will modulate the defense mechanism of the olfactory epithelium in different ways. Transient receptor potential vanilloid 1 (TRPV1), which is expressed in both nerves, maintains the regeneration ability of the olfactory epithelium. In this study, we investigated the role of TRPV1 against the nose-to-brain invasion of\n                      <jats:italic toggle=\"yes\">S. pneumoniae<\/jats:italic>\n                      . Six-week-old mice were treated with methimazole and\/or resiniferatoxin to ablate TRPV1 on the olfactory and trigeminal nerves, respectively. Bacterial density, cytokines\/chemokine induction, and histologic changes were investigated after intranasal infection with\n                      <jats:italic toggle=\"yes\">S. pneumoniae<\/jats:italic>\n                      . Olfactory epithelium ablation by methimazole increased intracranial invasion and mortality without bacteremia. Trigeminal TRPV1 ablation suppressed mortality. Intracranial invasion of\n                      <jats:italic toggle=\"yes\">S. pneumoniae<\/jats:italic>\n                      induced IL-6 in the olfactory bulb. Olfactory epithelium ablation was associated with significantly higher TNF-\u03b1 compared to trigeminal TRPV1 ablation. Intracranial invasion was suppressed by intranasal administration of a TRPV1 stimulant. TRPV1 on the olfactory nerve worked against intracranial invasion, whereas TRPV1 on the trigeminal nerve enhanced lethality via excessive cytokine\/chemokine production. The effect of intranasal TRPV1 stimulation was dominant on the olfactory nerve and could suppress central nervous system infection via the nose-to-brain route. The current finding can bring new strategies against infection targeting TRPV1.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        This study updates the current clinical concept of the pathogenesis of pneumococcal meningitis and bacteremia. The findings provide new insight into how the non-hematogenous nose-to-brain route is controlled via transient receptor potential vanilloid 1 (TRPV1) of the olfactory and trigeminal nerve. A mouse model demonstrates the non-hematogenous invasion of\n                        <jats:italic toggle=\"yes\">Streptococcus pneumoniae<\/jats:italic>\n                        from the nasal cavity directly into the cranium. TRPV1 on the olfactory nerve protected against intracranial invasion, whereas TRPV1 on the trigeminal nerve could induce a lethal course due to excessive inflammatory responses. Intranasal TRPV1 stimulation inhibited intracranial invasion and could control lethal central nervous system infection by\n                        <jats:italic toggle=\"yes\">S. pneumoniae<\/jats:italic>\n                        . These findings suggest a novel preventive strategy targeting TRPV1 against invasive pneumococcal infections.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.01335-25","type":"journal-article","created":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T12:00:27Z","timestamp":1755518427000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["Trigeminal TRPV1 regulates pneumococcal nose-to-brain invasion via IL-6\/TNF-\u03b1 signals"],"prefix":"10.1128","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-1995-9174","authenticated-orcid":false,"given":"Hideki","family":"Sakatani","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/005qv5373","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Otorhinolaryngology-Head and Neck Surgery, Wakayama Medical University","place":["Wakayama, 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