{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T09:06:45Z","timestamp":1790672805930,"version":"4.1.0"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Respiratory viral infections are increasingly recognized as important drivers of persistent airway symptoms and exacerbations in chronic lung disease. Post-infectious cough (PIC), particularly after upper respiratory tract infection, represents one of the most frequent causes of subacute cough and a mechanistically complex sequela in which cough hypersensitivity syndrome (CHS) plays a central pathophysiological role. Beyond increased cough frequency, patients with PIC frequently exhibit laryngeal sensory abnormalities and exaggerated responses to low-intensity stimuli, suggesting a sustained reduction in the activation threshold of airway sensory nerves. Among several contributors to cough hypersensitivity, P2X3 receptors and transient receptor potential (TRP) channels are key ion-channel targets mediating cough reflexes and sensory nerve hypersensitivity, yet their clinical translation has been heterogeneous. Gefapixant reduced objective cough frequency in phase III trials enrolling refractory or unexplained chronic cough populations, but these data provide indirect rather than PIC-specific evidence, and its clinical utility is limited by dysgeusia. Similarly, TRPV1 antagonists suppress capsaicin-provoked cough but have not consistently improved spontaneous cough frequency, highlighting a disconnect between provocation models and real-world post-infectious cough pathology. This review discusses how respiratory viruses may induce cough hypersensitivity through transcriptional, metabolic, and neuroimmune regulation of sensory pathways. Respiratory syncytial virus, rhinovirus, and other viral pathogens can upregulate TRPV1, TRPA1, and ASIC3 expression, while cytokines such as IFN-\u03b3 may promote sensory-neuron transcriptional reprogramming through JAK-STAT and NF-\u03baB signaling. In parallel, inflammatory mediators including bradykinin, COX\/12-LOX metabolites, and prostaglandin E2 can sensitize TRP channels through kinase-dependent phosphorylation, whereas virus-induced epithelial ATP release and impaired CD39\/CD73-mediated purinergic degradation may sustain repeated P2X3 receptor activation. Persistent peripheral afferent input may further induce central sensitization, explaining residual cough despite peripheral target blockade. By integrating viral immunopathogenesis, epithelial\u2013neural crosstalk, and ion-channel pharmacology, this review proposes a framework for understanding post-viral cough hypersensitivity as a neuroimmune sequela of respiratory infection. Future research should prioritize molecular endotype-based stratification, PIC-specific randomized controlled trials, optimization of highly selective P2X3 antagonists, and combined peripheral\u2013central assessment strategies to guide more precise therapeutic interventions.<\/jats:p>","DOI":"10.3389\/fphar.2026.1873086","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T08:37:21Z","timestamp":1790671041000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["From respiratory viral infection to persistent cough hypersensitivity: neuroimmune regulation and therapeutic implications of P2X3\/TRP ion-channel targets"],"prefix":"10.3389","volume":"17","author":[{"given":"Borui","family":"Li","sequence":"first","affiliation":[{"name":"Changchun University of Chinese Medicine","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyang","family":"Yu","sequence":"additional","affiliation":[{"name":"Changchun University of Chinese Medicine","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanshuai","family":"Zeng","sequence":"additional","affiliation":[{"name":"Jilin Provincial Center for Drug Review and Inspection","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaotian","family":"Jiang","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of Changchun University of Chinese Medicine","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haotian","family":"Xi","sequence":"additional","affiliation":[{"name":"Changchun University of Chinese Medicine","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Wang","sequence":"additional","affiliation":[{"name":"Changchun University of Chinese Medicine","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixiu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of Changchun University of Chinese Medicine","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1186\/s12931-019-1060-8","article-title":"Bradykinin sensitizes the cough reflex via a B(2) receptor dependent activation of TRPV1 and TRPA1 channels through metabolites of cyclooxygenase and 12-lipoxygenase","volume":"20","author":"Al-Shamlan","year":"2019","journal-title":"Respir. 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