{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T18:40:07Z","timestamp":1785177607637,"version":"3.55.0"},"reference-count":44,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,9,4]],"date-time":"2022-09-04T00:00:00Z","timestamp":1662249600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Chao Foundation"},{"name":"Mike Hogg Foundation"},{"name":"Brockman Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Of individuals who develop West Nile neuroinvasive disease (WNND), ~10% will die and &gt;40% will develop long-term complications. Current treatment recommendations solely focus on supportive care; therefore, we urgently need to identify novel and effective therapeutic options. We observed a correlation between substance P (SP), a key player in neuroinflammation, and its receptor Neurokinin-1 (NK1R). Our study in a wild-type BL6 mouse model found that SP is upregulated in the brain during infection, which correlated with neuroinvasion and damage to the blood\u2013brain barrier. Blocking the SP\/NK1R interaction beginning at disease onset modestly improved survival and prolonged time to death in a small pilot study. Although SP is significantly increased in the brain of untreated WNND mice when compared to mock-infected animals, levels of WNV are unchanged, indicating that SP likely does not play a role in viral replication but may mediate the immune response to infection. Additional studies are necessary to define if SP plays a mechanistic role or if it represents other mechanistic pathways.<\/jats:p>","DOI":"10.3390\/v14091961","type":"journal-article","created":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T20:50:27Z","timestamp":1662670227000},"page":"1961","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["A Potential Role for Substance P in West Nile Virus Neuropathogenesis"],"prefix":"10.3390","volume":"14","author":[{"given":"Shannon E.","family":"Ronca","sequence":"first","affiliation":[{"name":"Division of Tropical Medicine, Department of Pediatrics, National School of Tropical Medicine, Baylor College of Medicine and Texas Children\u2019s Hospital, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0648-6828","authenticated-orcid":false,"given":"Sarah M.","family":"Gunter","sequence":"additional","affiliation":[{"name":"Division of Tropical Medicine, Department of Pediatrics, National School of Tropical Medicine, Baylor College of Medicine and Texas Children\u2019s Hospital, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca Berry","family":"Kairis","sequence":"additional","affiliation":[{"name":"Division of Tropical Medicine, Department of Pediatrics, National School of Tropical Medicine, Baylor College of Medicine and Texas Children\u2019s Hospital, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison","family":"Lino","sequence":"additional","affiliation":[{"name":"Division of Tropical Medicine, Department of Pediatrics, National School of Tropical Medicine, Baylor College of Medicine and Texas Children\u2019s Hospital, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Romero","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7952-8526","authenticated-orcid":false,"given":"Robia G.","family":"Pautler","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Nimmo","sequence":"additional","affiliation":[{"name":"Centre for Molecular Therapeutics and College of Medicine and Dentistry, James Cook University, Cairns, QLD 4878, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristy O.","family":"Murray","sequence":"additional","affiliation":[{"name":"Division of Tropical Medicine, Department of Pediatrics, National School of Tropical Medicine, Baylor College of Medicine and Texas Children\u2019s Hospital, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"325","DOI":"10.3201\/eid2502.180765","article-title":"Cumulative Incidence of West Nile Virus Infection, Continental United States, 1999-2016","volume":"25","author":"Ronca","year":"2019","journal-title":"Emerg. Infect. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/S0140-6736(01)05480-0","article-title":"Epidemic West Nile encephalitis, New York, 1999: Results of a household-based seroepidemiological survey","volume":"358","author":"Mostashari","year":"2001","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"684","DOI":"10.3201\/eid1804.111313","article-title":"Neuroinvasive disease and West Nile virus infection, North Dakota, USA, 1999\u20132008","volume":"18","author":"Carson","year":"2012","journal-title":"Emerg. Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.4269\/ajtmh.14-0616","article-title":"Long-term neurological outcomes in West Nile virus-infected patients: An observational study","volume":"92","author":"Weatherhead","year":"2015","journal-title":"Am. J. Trop Med. Hyg."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1086\/503038","article-title":"West Nile virus disease: A descriptive study of 228 patients hospitalized in a 4-county region of Colorado in 2003","volume":"42","author":"Bode","year":"2006","journal-title":"Clin. Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"606","DOI":"10.3390\/v6020606","article-title":"Clinical manifestations and outcomes of West Nile virus infection","volume":"6","author":"Sejvar","year":"2014","journal-title":"Viruses"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Erickson, T.A., Ronca, S.E., Gunter, S.M., Brown, E.L., Hasbun, R., and Murray, K.O. (2022). Zoonotic Disease Testing Practices in Pediatric Patients with Meningitis and Encephalitis in a Subtropical Region. Pathogens, 11.","DOI":"10.3390\/pathogens11050501"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1587","DOI":"10.3201\/eid2209.152050","article-title":"Use of Testing for West Nile Virus and Other Arboviruses","volume":"22","author":"Vanichanan","year":"2016","journal-title":"Emerg. Infect. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1053\/hp.2000.8047","article-title":"The pathology of human West Nile Virus infection","volume":"31","author":"Sampson","year":"2000","journal-title":"Hum. Pathol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1111\/j.1749-6632.2001.tb02695.x","article-title":"West Nile encephalitis: The neuropathology of four fatalities","volume":"951","author":"Sampson","year":"2001","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1111\/j.1749-6632.2010.05826.x","article-title":"Neurokinin-1 receptor: Functional significance in the immune system in reference to selected infections and inflammation","volume":"1217","author":"Douglas","year":"2011","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/S0165-5728(02)00262-X","article-title":"Substance P antagonist blocks leakage and reduces activation of cytokine-stimulated rat brain endothelium","volume":"131","author":"Annunziata","year":"2002","journal-title":"J. Neuroimmunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1111\/bph.13155","article-title":"Inflammation in acute CNS injury: A focus on the role of substance P","volume":"173","author":"Corrigan","year":"2016","journal-title":"Br. J. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"578480","DOI":"10.1155\/2013\/578480","article-title":"Blocking neurogenic inflammation for the treatment of acute disorders of the central nervous system","volume":"2013","author":"Lewis","year":"2013","journal-title":"Int. J. Inflamm."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.nurt.2009.10.016","article-title":"Involvement of pro- and anti-inflammatory cytokines and chemokines in the pathophysiology of traumatic brain injury","volume":"7","author":"Ziebell","year":"2010","journal-title":"Neurotherapeutics"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3651","DOI":"10.1128\/IAI.00358-08","article-title":"Interleukin-12 (IL-12) and IL-23 induction of substance p synthesis in murine T cells and macrophages is subject to IL-10 and transforming growth factor beta regulation","volume":"76","author":"Blum","year":"2008","journal-title":"Infect. Immun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.1038\/jcbfm.2009.63","article-title":"Substance P is associated with the development of brain edema and functional deficits after traumatic brain injury","volume":"29","author":"Donkin","year":"2009","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1007\/s00726-006-0335-9","article-title":"The role of substance P in stress and anxiety responses","volume":"31","author":"Ebner","year":"2006","journal-title":"Amino Acids"},{"key":"ref_19","first-page":"296","article-title":"The Therapeutic Potential of Targeting Substance P\/NK-1R Interactions in Inflammatory CNS Disorders","volume":"10","author":"Johnson","year":"2016","journal-title":"Front. Cell. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"G839","DOI":"10.1152\/ajpgi.00436.2012","article-title":"Substance P is essential for maintaining gut muscle contractility: A novel role for coneurotransmission revealed by botulinum toxin","volume":"306","author":"Li","year":"2014","journal-title":"Am. J. Physiol. Gastrointest Liver Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4249","DOI":"10.1007\/s00018-016-2293-z","article-title":"Neuropeptide substance P and the immune response","volume":"73","author":"Mashaghi","year":"2016","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"C1586","DOI":"10.1152\/ajpcell.00129.2008","article-title":"Substance P enhances NF-kappaB transactivation and chemokine response in murine macrophages via ERK1\/2 and p38 MAPK signaling pathways","volume":"294","author":"Sun","year":"2008","journal-title":"Am. J. Physiol. Cell. Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1159\/000363041","article-title":"Activation of microglia by histamine and substance P","volume":"34","author":"Zhu","year":"2014","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/s12974-017-0813-x","article-title":"Aprepitant limits in vivo neuroinflammatory responses in a rhesus model of Lyme neuroborreliosis","volume":"14","author":"Martinez","year":"2017","journal-title":"J. Neuroinflamm."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1186\/s12974-015-0453-y","article-title":"Antagonist of the neurokinin-1 receptor curbs neuroinflammation in ex vivo and in vitro models of Lyme neuroborreliosis","volume":"12","author":"Martinez","year":"2015","journal-title":"J. Neuroinflamm."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.2353\/ajpath.2010.091109","article-title":"Neurokinin-1 receptor (NK1-R) expression in the brains of SIV-infected rhesus macaques: Implications for substance P in NK1-R immune cell trafficking into the CNS","volume":"177","author":"Alvarez","year":"2010","journal-title":"Am. J. Pathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1016\/j.bmcl.2005.11.047","article-title":"Design and synthesis of a novel, achiral class of highly potent and selective, orally active neurokinin-1 receptor antagonists","volume":"16","author":"Hoffmann","year":"2006","journal-title":"Bioorg Med. Chem. Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.jviromet.2014.02.026","article-title":"Development of generic Taqman PCR and RT-PCR assays for the detection of DNA and mRNA of beta-actin-encoding sequences in a wide range of animal species","volume":"202","author":"Piorkowski","year":"2014","journal-title":"J. Virol. Methods"},{"key":"ref_29","first-page":"A404","article-title":"West Nile meningitis\/encephalitis: Experience with corticosteroid therapy","volume":"62","author":"Narayanaswami","year":"2004","journal-title":"Neurology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"43","DOI":"10.7812\/TPP\/09-028","article-title":"Successful treatment with intravenous immunoglobulin of acute flaccid paralysis caused by west nile virus","volume":"13","author":"Walid","year":"2009","journal-title":"Perm. J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1586\/14760584.2014.906309","article-title":"Current trends in West Nile virus vaccine development","volume":"13","author":"Amanna","year":"2014","journal-title":"Expert Rev. Vaccines"},{"key":"ref_32","first-page":"289","article-title":"West Nile virus infection: MR imaging findings in the nervous system","volume":"26","author":"Ali","year":"2005","journal-title":"AJNR Am. J. Neuroradiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1097\/01.cnd.0000496973.95654.fd","article-title":"MRI Ventral Nerve Root Enhancement in Five Patients Presenting With Extremity Weakness Secondary to Neuroinvasive West Nile Virus","volume":"18","author":"Patel","year":"2016","journal-title":"J. Clin. Neuromuscul. Dis."},{"key":"ref_34","first-page":"4389691","article-title":"A Case of West Nile Encephalitis That Develops into a Disease of Deep White Matter on MRI over a Two-Week Span","volume":"2016","author":"Puchalski","year":"2016","journal-title":"Case Rep. Neurol. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"111","DOI":"10.3389\/fneur.2018.00111","article-title":"The Neurocognitive and MRI Outcomes of West Nile Virus Infection: Preliminary Analysis Using an External Control Group","volume":"9","author":"Murray","year":"2018","journal-title":"Front. Neurol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/s41398-018-0163-1","article-title":"Association between amygdala neurokinin-1 receptor availability and anxiety-related personality traits","volume":"8","author":"Hoppe","year":"2018","journal-title":"Transl. Psychiatry"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4280","DOI":"10.1073\/pnas.0400794101","article-title":"Substance P in the medial amygdala: Emotional stress-sensitive release and modulation of anxiety-related behavior in rats","volume":"101","author":"Ebner","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"275","DOI":"10.2165\/00023210-200519040-00001","article-title":"Substance P receptor antagonists in psychiatry: Rationale for development and therapeutic potential","volume":"19","author":"Herpfer","year":"2005","journal-title":"CNS Drugs"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Kahnau, P., Habedank, A., Diederich, K., and Lewejohann, L. (2020). Behavioral Methods for Severity Assessment. Animals, 10.","DOI":"10.3390\/ani10071136"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Hohlbaum, K., Bert, B., Dietze, S., Palme, R., Fink, H., and Thone-Reineke, C. (2017). Severity classification of repeated isoflurane anesthesia in C57BL\/6JRj mice-Assessing the degree of distress. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0179588"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"119423","DOI":"10.1016\/j.lfs.2021.119423","article-title":"Lasting effects of ketamine and isoflurane administration on anxiety- and panic-like behavioral responses in Wistar rats","volume":"276","author":"Chirico","year":"2021","journal-title":"Life Sci."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Yonezaki, K., Uchimoto, K., Miyazaki, T., Asakura, A., Kobayashi, A., Takase, K., and Goto, T. (2015). Postanesthetic effects of isoflurane on behavioral phenotypes of adult male C57BL\/6J mice. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0122118"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1543","DOI":"10.4049\/jimmunol.1601751","article-title":"Role of Substance P Neuropeptide in Inflammation, Wound Healing, and Tissue Homeostasis","volume":"199","author":"Suvas","year":"2017","journal-title":"J. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1007\/s11481-015-9589-x","article-title":"Reciprocal Regulation of Substance P and IL-12\/IL-23 and the Associated Cytokines, IFNgamma\/IL-17: A Perspective on the Relevance of This Interaction to Multiple Sclerosis","volume":"10","author":"Vilisaar","year":"2015","journal-title":"J. Neuroimmune Pharmacol."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/9\/1961\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:23:06Z","timestamp":1760142186000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/9\/1961"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,4]]},"references-count":44,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["v14091961"],"URL":"https:\/\/doi.org\/10.3390\/v14091961","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,4]]}}}