{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T10:31:22Z","timestamp":1790937082578,"version":"4.1.0"},"posted":{"date-parts":[[2025,6,29]]},"group-title":"Neuroscience","reference-count":62,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,6,29]],"date-time":"2025-06-29T00:00:00Z","timestamp":1751155200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"funder":[{"award":["AI158688"],"award-info":[{"award-number":["AI158688"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["AI159402"],"award-info":[{"award-number":["AI159402"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["NS130608"],"award-info":[{"award-number":["NS130608"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,6,29]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Cough is a hallmark sign of tuberculosis and key driver of transmission. While traditionally attributed to host-driven inflammation, we previously demonstrated that\n                  <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                  lipid extract (Mtb extract) and its component sulfolipid-1 (SL-1) directly activate nociceptive neurons to induce cough in guinea pigs. However, the cellular mechanisms by which Mtb extract and SL-1 modulate nociceptive sensory neurons remain incompletely understood. Here, we show that Mtb extract enhances action potential (AP) generation in mouse nodose nociceptors via an SL-1\u2013dependent mechanism. Using calcium imaging, we found that Mtb extract and SL-1 increased intracellular Ca\u00b2\u207a signals in TRPV1\u207a neurons from both mouse nodose and human dorsal root ganglia (hDRG). These Ca\u00b2\u207a signals were attenuated by the G\u03b1q\/11 pathway inhibitor YM254890, even in the absence of extracellular Ca\u00b2\u207a, suggesting involvement of intracellular Ca\u00b2\u207a stores. Together, these findings indicate that SL-1 engages G\u03b1q\/11-coupled pathways to sensitize nociceptors via intracellular Ca\n                  <jats:sup>2+<\/jats:sup>\n                  release, providing mechanistic insight into tuberculosis-associated cough and potential targets for therapeutic intervention.\n                <\/jats:p>","DOI":"10.1101\/2025.06.28.662105","type":"posted-content","created":{"date-parts":[[2025,6,29]],"date-time":"2025-06-29T21:20:13Z","timestamp":1751232013000},"source":"Crossref","is-referenced-by-count":2,"title":["<i>Mycobacterium tuberculosis<\/i>\n                  sulfolipid-1 (Sl-1) increases the excitability of mouse and human TRPV1-positive sensory neurons in a YM254890-reversible fashion"],"prefix":"10.64898","author":[{"given":"Dhananjay K.","family":"Naik","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felipe","family":"Espinosa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ifunanya M.","family":"Okolie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kubra F.","family":"Naqvi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giaochau","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cody R.","family":"Ruhl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven","family":"Kroener","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"Dussor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4329-2253","authenticated-orcid":false,"given":"Michael U.","family":"Shiloh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6971-6221","authenticated-orcid":false,"given":"Theodore J.","family":"Price","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025070203150720000_2025.06.28.662105v1.1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adj9173)"},{"key":"2025070203150720000_2025.06.28.662105v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pupt.2017.06.009"},{"key":"2025070203150720000_2025.06.28.662105v1.3","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-61779-126-0_15"},{"key":"2025070203150720000_2025.06.28.662105v1.4","doi-asserted-by":"publisher","DOI":"10.1186\/1745-9974-7-10"},{"key":"2025070203150720000_2025.06.28.662105v1.5","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf8156"},{"key":"2025070203150720000_2025.06.28.662105v1.6","doi-asserted-by":"crossref","unstructured":"Burnstock, G . (2006). Historical review: ATP as a neurotransmitter. In Trends in Pharmacological Sciences (Elsevier Ltd), pp. 166\u2013176.","DOI":"10.1016\/j.tips.2006.01.005"},{"key":"2025070203150720000_2025.06.28.662105v1.7","doi-asserted-by":"crossref","unstructured":"Burnstock, G. , Brouns, I. , Adriaensen, D. , and Timmermans, J.P. (2012). Purinergic signaling in the airways. In Pharmacological Reviews, pp. 834\u2013868.","DOI":"10.1124\/pr.111.005389"},{"key":"2025070203150720000_2025.06.28.662105v1.8","doi-asserted-by":"publisher","DOI":"10.1006\/pupt.2002.0363"},{"key":"2025070203150720000_2025.06.28.662105v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.pupt.2006.12.003"},{"key":"2025070203150720000_2025.06.28.662105v1.10","doi-asserted-by":"publisher","DOI":"10.1007\/s00408-007-9054-6"},{"key":"2025070203150720000_2025.06.28.662105v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.pupt.2011.01.008"},{"key":"2025070203150720000_2025.06.28.662105v1.12","doi-asserted-by":"publisher","DOI":"10.1378\/chest.14-1481"},{"key":"2025070203150720000_2025.06.28.662105v1.13","doi-asserted-by":"crossref","unstructured":"Canning, B.J. , and Spina, D . (2009). Sensory nerves and airway irritability. Handb Exp Pharmacol, 139\u2013183.","DOI":"10.1007\/978-3-540-79090-7_5"},{"key":"2025070203150720000_2025.06.28.662105v1.14","doi-asserted-by":"publisher","DOI":"10.1038\/39807"},{"key":"2025070203150720000_2025.06.28.662105v1.15","doi-asserted-by":"publisher","DOI":"10.1038\/nature12479"},{"key":"2025070203150720000_2025.06.28.662105v1.16","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1030024100"},{"key":"2025070203150720000_2025.06.28.662105v1.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2020.109717"},{"key":"2025070203150720000_2025.06.28.662105v1.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2025.108426"},{"key":"2025070203150720000_2025.06.28.662105v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2025.102541"},{"key":"2025070203150720000_2025.06.28.662105v1.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.chest.2017.11.018"},{"key":"2025070203150720000_2025.06.28.662105v1.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.pupt.2008.12.022"},{"key":"2025070203150720000_2025.06.28.662105v1.22","doi-asserted-by":"crossref","unstructured":"Garcia-Vilanova, A. , Chan, J. , and Torrelles, J.B . (2019). Underestimated Manipulative Roles of Mycobacterium tuberculosis Cell Envelope Glycolipids During Infection. Frontiers in Immunology 10.","DOI":"10.3389\/fimmu.2019.02909"},{"key":"2025070203150720000_2025.06.28.662105v1.23","doi-asserted-by":"publisher","DOI":"10.5588\/ijtld.22.0511"},{"key":"2025070203150720000_2025.06.28.662105v1.24","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00188.2020"},{"key":"2025070203150720000_2025.06.28.662105v1.25","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0100984"},{"key":"2025070203150720000_2025.06.28.662105v1.26","doi-asserted-by":"crossref","unstructured":"Kim, S.H. , Patil, M.J. , Hadley, S.H. , Bahia, P.K. , Butler, S.G. , Madaram, M. , and Taylor-Clark, T.E . (2022). Mapping of the sensory innervation of the mouse lung by specific vagal and dorsal root ganglion neuronal subsets. eNeuro.","DOI":"10.1523\/ENEURO.0026-22.2022"},{"key":"2025070203150720000_2025.06.28.662105v1.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.04.096"},{"key":"2025070203150720000_2025.06.28.662105v1.28","first-page":"1137","article-title":"Cough Frequency in Patients with Respiratory Disease","volume":"96","year":"1967","journal-title":"American Review of Respiratory Disease"},{"key":"2025070203150720000_2025.06.28.662105v1.29","first-page":"109","article-title":"Cough Frequency and Infectivity in Patients with Pulmonary Tuberculosis","volume":"99","year":"1969","journal-title":"American Review of Respiratory Disease"},{"key":"2025070203150720000_2025.06.28.662105v1.30","doi-asserted-by":"crossref","unstructured":"Maher, D . (2009). Chapter 13 - The natural history of Mycobacterium tuberculosis infection in adults. 129-132.","DOI":"10.1016\/B978-1-4160-3988-4.00013-5"},{"key":"2025070203150720000_2025.06.28.662105v1.31","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2018.09.004"},{"key":"2025070203150720000_2025.06.28.662105v1.32","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00117.2012"},{"key":"2025070203150720000_2025.06.28.662105v1.33","doi-asserted-by":"crossref","unstructured":"Migliori, G.B. , Ong, C.W.M. , Petrone, L. , D\u2019ambrosio, L. , Centis, R. , and Goletti, D. (2021). The definition of tuberculosis infection based on the spectrum of tuberculosis disease. In Breathe (European Respiratory Society).","DOI":"10.1183\/20734735.0079-2021"},{"key":"2025070203150720000_2025.06.28.662105v1.34","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb802"},{"key":"2025070203150720000_2025.06.28.662105v1.35","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0220-17.2017"},{"key":"2025070203150720000_2025.06.28.662105v1.36","doi-asserted-by":"publisher","DOI":"10.1210\/en.143.2.569"},{"key":"2025070203150720000_2025.06.28.662105v1.37","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-031422-092315"},{"key":"2025070203150720000_2025.06.28.662105v1.38","first-page":"S712","article-title":"Afferent neural pathways mediating cough in animals and humans","volume":"6","year":"2014","journal-title":"J Thorac Dis"},{"key":"2025070203150720000_2025.06.28.662105v1.39","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2024.1386645"},{"key":"2025070203150720000_2025.06.28.662105v1.40","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00494.2009"},{"key":"2025070203150720000_2025.06.28.662105v1.41","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-023-01067-0"},{"key":"2025070203150720000_2025.06.28.662105v1.42","doi-asserted-by":"crossref","unstructured":"Patterson, B. , and Wood, R . (2019). Is cough really necessary for TB transmission? In Tuberculosis (Churchill Livingstone), pp. 31\u201335.","DOI":"10.1016\/j.tube.2019.05.003"},{"key":"2025070203150720000_2025.06.28.662105v1.43","first-page":"503.507","article-title":"YM-254890 is a General Inhibitor of G Proteins","volume":"33","year":"2019","journal-title":"The FASEB Journal"},{"key":"2025070203150720000_2025.06.28.662105v1.44","doi-asserted-by":"publisher","DOI":"10.1084\/jem.45.6.1025"},{"key":"2025070203150720000_2025.06.28.662105v1.45","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20225568"},{"key":"2025070203150720000_2025.06.28.662105v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.02.026"},{"key":"2025070203150720000_2025.06.28.662105v1.47","unstructured":"Seabra, B. , and Duarte, R. (2021). Tuberculosis national registries and data on diagnosis delay \u2013 Is there room for improvement? Pulmonology."},{"key":"2025070203150720000_2025.06.28.662105v1.48","first-page":"1","article-title":"Predictors of Re-Emerging Tuberculosis: A Review","volume":"03","year":"2016","journal-title":"OALib"},{"key":"2025070203150720000_2025.06.28.662105v1.49","unstructured":"Shiers, S. et. al. (2022). Human Ganglia and Spinal Cord Tissue Procurement from Organ Donors and Tissue Quality Assessment. protocolsio."},{"key":"2025070203150720000_2025.06.28.662105v1.50","doi-asserted-by":"crossref","unstructured":"Singh, N. , Driessen, A.K. , McGovern, A.E. , Moe, A.A.K. , Farrell, M.J. , and Mazzone, S.B . (2020). Peripheral and central mechanisms of cough hypersensitivity. Paper presented at: Journal of Thoracic Disease (AME Publishing Company).","DOI":"10.21037\/jtd-2020-icc-007"},{"key":"2025070203150720000_2025.06.28.662105v1.51","doi-asserted-by":"crossref","first-page":"S11","DOI":"10.1016\/j.jpain.2005.01.042","article-title":"Activation of the phosphoinositide 3-Kinase - Akt\/PKB signaling pathway in primary sensory neurons after peripheral inflammation contributes to inflammatory mechanical hyperalgesia","volume":"6","year":"2005","journal-title":"The Journal of Pain"},{"key":"2025070203150720000_2025.06.28.662105v1.52","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2015.06.007"},{"key":"2025070203150720000_2025.06.28.662105v1.53","doi-asserted-by":"crossref","unstructured":"Tavares-Ferreira, D. , Shiers, S. , Ray, P.R. , Wangzhou, A. , Jeevakumar, V. , Sankaranarayanan, I. , Cervantes, A.M. , Reese, J.C. , Chamessian, A. , Copits, B.A. , et al. (2022). Spatial transcriptomics of dorsal root ganglia identifies molecular signatures of human nociceptors. Sci Transl Med 14, eabj8186.","DOI":"10.1126\/scitranslmed.abj8186"},{"key":"2025070203150720000_2025.06.28.662105v1.54","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80564-4"},{"key":"2025070203150720000_2025.06.28.662105v1.55","doi-asserted-by":"crossref","unstructured":"Trent, T. , Miller, J.J. , and Bowman, G.R. (2024). The G protein inhibitor YM-254890 is an allosteric glue. bioRxiv.","DOI":"10.1101\/2024.11.25.625299"},{"key":"2025070203150720000_2025.06.28.662105v1.56","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiu625"},{"key":"2025070203150720000_2025.06.28.662105v1.57","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3881"},{"key":"2025070203150720000_2025.06.28.662105v1.58","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1995.75.4.865"},{"key":"2025070203150720000_2025.06.28.662105v1.59","doi-asserted-by":"publisher","DOI":"10.3109\/10799890903295150"},{"key":"2025070203150720000_2025.06.28.662105v1.60","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2016.12.023"},{"key":"2025070203150720000_2025.06.28.662105v1.61","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-024-01794-1"},{"key":"2025070203150720000_2025.06.28.662105v1.62","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2893-04.2004"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.06.28.662105","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T09:01:50Z","timestamp":1768467710000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.06.28.662105"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,29]]},"references-count":62,"URL":"https:\/\/doi.org\/10.1101\/2025.06.28.662105","relation":{},"subject":[],"published":{"date-parts":[[2025,6,29]]},"subtype":"preprint"}}