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Despite the fact that the role of NS1 proteins from various mosquito-borne flaviviruses in pathogenesis and their ability to affect human endothelial permeability have been investigated, TBEV NS1 has thus far been insufficiently studied. In this study, human endothelial permeability was assessed using TEER and transwell permeability assays. Signaling pathways were determined by RNAseq. The ability of the NS1 protein of TBEV to affect human endothelial permeability was investigated for the first time. It was shown that recombinant TBEV NS1 produced in eucaryotic cells directly affected human lung microvascular endothelial cells (HLMVECs) in vitro but not human umbilical vein endothelial cells (HUVECs). It was indicated that TBEV NS1 induced endothelial hyperpermeability of HLMVECs through activating TNF-\u03b1 and other inflammatory signaling pathways.<\/jats:p>","DOI":"10.3390\/ijms26115311","type":"journal-article","created":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T11:40:32Z","timestamp":1748864432000},"page":"5311","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["TBEV NS1 Induces Tissue-Specific Microvascular Endothelial Cell Permeability by Activating the TNF-\u03b1 Signaling Pathway"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1413-5876","authenticated-orcid":false,"given":"Yana","family":"Khlusevich","sequence":"first","affiliation":[{"name":"Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2066-8975","authenticated-orcid":false,"given":"Bogdana","family":"Kravchuk","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4822-0251","authenticated-orcid":false,"given":"Andrey","family":"Kechin","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alena","family":"Stepanova","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8799-7135","authenticated-orcid":false,"given":"Lyudmila","family":"Emelyanova","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sargis","family":"Khachatryan","sequence":"additional","affiliation":[{"name":"State Budgetary Healthcare Institution of the Novosibirsk Region, \u201cState Novosibirsk Regional Clinical Hospital\u201d, 630087 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Tikunova","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6884-6104","authenticated-orcid":false,"given":"Andrey","family":"Matveev","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.antiviral.2019.01.014","article-title":"Tick-Borne Encephalitis in Europe and Russia: Review of Pathogenesis, Clinical Features, Therapy, and Vaccines","volume":"164","author":"Ruzek","year":"2019","journal-title":"Antivir. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e2470","DOI":"10.1002\/rmv.2470","article-title":"Tick-Borne Encephalitis: A Comprehensive Review of the Epidemiology, Virology, and Clinical Picture","volume":"33","author":"Chiffi","year":"2023","journal-title":"Rev. Med. Virol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Li\u010dkov\u00e1, M., Fuma\u010dov\u00e1 Havl\u00edkov\u00e1, S., Sl\u00e1vikov\u00e1, M., and Klempa, B. (2022). Alimentary Infections by Tick-Borne Encephalitis Virus. Viruses, 14.","DOI":"10.3390\/v14010056"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Michelitsch, A., Wernike, K., Klaus, C., Dobler, G., and Beer, M. (2019). Exploring the Reservoir Hosts of Tick-Borne Encephalitis Virus. Viruses, 11.","DOI":"10.3390\/v11070669"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2619","DOI":"10.3390\/microbiolres15040174","article-title":"Tick-Borne Encephalitis Virus (TBEV): Epidemiology, Diagnosis, Therapeutic Approaches and Some Molecular Aspects\u2014An Updated Review","volume":"15","author":"Mittova","year":"2024","journal-title":"Microbiol. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.ttbdis.2014.09.002","article-title":"Full Genome Sequences and Molecular Characterization of Tick-Borne Encephalitis Virus Strains Isolated from Human Patients","volume":"6","author":"Kozlova","year":"2015","journal-title":"Ticks Tick-Borne Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"593","DOI":"10.2217\/fvl.10.39","article-title":"Structural and Functional Parameters of the Flaviviral Protease: A Promising Antiviral Drug Target","volume":"5","author":"Shiryaev","year":"2010","journal-title":"Future Virol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"12895","DOI":"10.1128\/JVI.00942-09","article-title":"Crystal Structure of a Novel Conformational State of the Flavivirus NS3 Protein: Implications for Polyprotein Processing and Viral Replication","volume":"83","author":"Assenberg","year":"2009","journal-title":"J. Virol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1021\/acsinfecdis.3c00566","article-title":"Roles of NS1 Protein in Flavivirus Pathogenesis","volume":"10","author":"Perera","year":"2024","journal-title":"ACS Infect. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Fisher, R., Lustig, Y., Sklan, E.H., and Schwartz, E. (2023). The Role of NS1 Protein in the Diagnosis of Flavivirus Infections. Viruses, 15.","DOI":"10.3390\/v15020572"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.virol.2011.02.022","article-title":"N-Linked Glycosylation of Dengue Virus NS1 Protein Modulates Secretion, Cell-Surface Expression, Hexamer Stability, and Interactions with Human Complement","volume":"413","author":"Somnuke","year":"2011","journal-title":"Virology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"304ra142","DOI":"10.1126\/scitranslmed.aaa3863","article-title":"Dengue Virus NS1 Protein Activates Cells via Toll-like Receptor 4 and Disrupts Endothelial Cell Monolayer Integrity","volume":"7","author":"Modhiran","year":"2015","journal-title":"Sci. Transl. Med"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1084\/jem.20092545","article-title":"Antagonism of the Complement Component C4 by Flavivirus Nonstructural Protein NS1","volume":"207","author":"Avirutnan","year":"2010","journal-title":"J. Exp. Med."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Conde, J.N., Silva, E.M., Barbosa, A.S., and Mohana-Borges, R. (2017). The Complement System in Flavivirus Infections. Front. Microbiol., 8.","DOI":"10.3389\/fmicb.2017.00213"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1007\/s12250-014-3459-1","article-title":"Critical Role of Dengue Virus NS1 Protein in Viral Replication","volume":"29","author":"Fan","year":"2014","journal-title":"Virol. Sin."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1186\/s12985-016-0590-7","article-title":"Flavivirus NS1: A Multifaceted Enigmatic Viral Protein","volume":"13","author":"Rastogi","year":"2016","journal-title":"Virol. J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1126\/science.1247749","article-title":"Flavivirus NS1 Crystal Structures Reveal a Surface for Membrane Association and Regions of Interaction with the Immune System","volume":"343","author":"Akey","year":"2014","journal-title":"Science"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2492","DOI":"10.1099\/vir.0.83620-0","article-title":"Association of Dengue Virus NS1 Protein with Lipid Rafts","volume":"89","author":"Noisakran","year":"2008","journal-title":"J. Gen. Virol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1007\/s007050050127","article-title":"The Dengue Virus Nonstructural-1 Protein (NS1) Generates Antibodies to Common Epitopes on Human Blood Clotting, Integrin\/Adhesin Proteins and Binds to Human Endothelial Cells: Potential Implications in Haemorrhagic Fever Pathogenesis","volume":"142","author":"Falconar","year":"1997","journal-title":"Arch. Virol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1086\/342600","article-title":"Facilitation of Cell Adhesion by Immobilized Dengue Viral Nonstructural Protein 1 (NS1): Arginine-Glycine-Aspartic Acid Structural Mimicry within the Dengue Viral NS1 Antigen","volume":"186","author":"Chang","year":"2002","journal-title":"J. Infect. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1016\/j.celrep.2019.01.036","article-title":"Flavivirus NS1 Triggers Tissue-Specific Vascular Endothelial Dysfunction Reflecting Disease Tropism","volume":"26","author":"Glasner","year":"2019","journal-title":"Cell Rep."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Wang, C., Puerta-Guardo, H., Biering, S.B., Glasner, D.R., Tran, E.B., Patana, M., Gomberg, T.A., Malvar, C., Lo, N.T.N., and Espinosa, D.A. (2019). Endocytosis of Flavivirus NS1 Is Required for NS1-Mediated Endothelial Hyperpermeability and Is Abolished by a Single N-Glycosylation Site Mutation. PLoS Pathog., 15.","DOI":"10.1371\/journal.ppat.1007938"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.virusres.2005.04.007","article-title":"Steps of the Tick-Borne Encephalitis Virus Replication Cycle That Affect Neuropathogenesis","volume":"111","author":"Mandl","year":"2005","journal-title":"Virus. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"106031","DOI":"10.1016\/j.pep.2021.106031","article-title":"Tick-Borne Encephalitis Nonstructural Protein NS1 Expressed in E. Coli Retains Immunological Properties of the Native Protein","volume":"191","author":"Andrey","year":"2022","journal-title":"Protein Expr. Purif."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Matveev, A., Pyankov, O., Khlusevich, Y., Tyazhelkova, O., Emelyanova, L., Timofeeva, A., Shipovalov, A., Chechushkov, A., Zaitseva, N., and Kudrov, G. (2023). Antibodies Capable of Enhancing SARS-CoV-2 Infection Can Circulate in Patients with Severe COVID-19. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241310799"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"101927","DOI":"10.1016\/j.ttbdis.2022.101927","article-title":"Occurrence and Clinical Manifestations of Tick-Borne Rickettsioses in Western Siberia: First Russian Cases of Rickettsia Aeschlimannii and Rickettsia Slovaca Infections","volume":"13","author":"Igolkina","year":"2022","journal-title":"Ticks Tick-Borne Dis."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Kravchuk, B.I., Khlusevich, Y.A., Chicherina, G.S., Yakimenko, V.V., Krasnova, E.I., Tikunova, N.N., and Matveev, A.L. (2024). Cross-Reactive Antibodies to the NS1 Protein of Omsk Hemorrhagic Fever Virus Are Absent in the Sera of Patients with Tick-Borne Encephalitis. Viruses, 16.","DOI":"10.20944\/preprints202405.0626.v1"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1006\/viro.1996.0261","article-title":"Importance of Localized Skin Infection in Tick-Borne Encephalitis Virus Transmission","volume":"219","author":"Labuda","year":"1996","journal-title":"Virology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"15","DOI":"10.3109\/00365549509018965","article-title":"Prevalence of Antibodies against Tick-Borne Encephalitis among Residents of North-Eastern Poland","volume":"27","author":"Prokopowicz","year":"1995","journal-title":"Scand. J. Infect. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1124\/pr.57.2.4","article-title":"The Blood-Brain Barrier\/Neurovascular Unit in Health and Disease","volume":"57","author":"Hawkins","year":"2005","journal-title":"Pharmacol. Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"20720","DOI":"10.2807\/1560-7917.ES2014.19.9.20720","article-title":"Zika Virus Infection Complicated by Guillain-Barre Syndrome\u2014Case Report, French Polynesia, December 2013","volume":"19","author":"Oehler","year":"2014","journal-title":"Euro Surveill."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Ayala-Nunez, N.V., and Gaudin, R. (2020). A Viral Journey to the Brain: Current Considerations and Future Developments. PLoS Pathog., 16.","DOI":"10.1371\/journal.ppat.1008434"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Hsieh, J.T., and St John, A.L. (2020). Japanese Encephalitis Virus and Its Mechanisms of Neuroinvasion. PLoS Pathog., 16.","DOI":"10.1371\/journal.ppat.1008260"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1177\/1753425920954281","article-title":"Immune Response and Blood-Brain Barrier Dysfunction during Viral Neuroinvasion","volume":"27","author":"Chen","year":"2021","journal-title":"Innate Immun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e3257","DOI":"10.1097\/MD.0000000000003257","article-title":"Guillain-Barr\u00e9 Syndrome (42 Cases) Occurring During a Zika Virus Outbreak in French Polynesia","volume":"95","author":"Watrin","year":"2016","journal-title":"Medicine"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e00009-17","DOI":"10.1128\/JVI.00009-17","article-title":"Animal Models of Zika Virus Infection, Pathogenesis, and Immunity","volume":"91","author":"Morrison","year":"2017","journal-title":"J. Virol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.jinf.2014.05.010","article-title":"Flaviviruses Are Neurotropic, but How Do They Invade the CNS?","volume":"69","author":"Neal","year":"2014","journal-title":"J. Infect."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1099\/vir.0.040899-0","article-title":"West Nile Virus-Induced Disruption of the Blood\u2013Brain Barrier in Mice Is Characterized by the Degradation of the Junctional Complex Proteins and Increase in Multiple Matrix Metalloproteinases","volume":"93","author":"Roe","year":"2012","journal-title":"J. Gen. Virol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5602","DOI":"10.1128\/JVI.00143-15","article-title":"Viral Infection of the Central Nervous System and Neuroinflammation Precede Blood-Brain Barrier Disruption during Japanese Encephalitis Virus Infection","volume":"89","author":"Li","year":"2015","journal-title":"J. Virol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"R\u016f\u017eek, D., Sal\u00e1t, J., Singh, S.K., and Kopeck\u00fd, J. (2011). Breakdown of the Blood-Brain Barrier during Tick-Borne Encephalitis in Mice Is Not Dependent on CD8+ T-Cells. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0020472"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"12202","DOI":"10.1128\/JVI.01215-14","article-title":"Type I Interferon Protects Mice from Fatal Neurotropic Infection with Langat Virus by Systemic and Local Antiviral Responses","volume":"88","author":"Weber","year":"2014","journal-title":"J. Virol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/s12974-016-0487-9","article-title":"Type I Interferon Response in Olfactory Bulb, the Site of Tick-Borne Flavivirus Accumulation, Is Primarily Regulated by IPS-1","volume":"13","author":"Kurhade","year":"2016","journal-title":"J. Neuroinflamm."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.virol.2017.04.012","article-title":"Tick-Borne Encephalitis Virus Infects Human Brain Microvascular Endothelial Cells without Compromising Blood-Brain Barrier Integrity","volume":"507","author":"Palus","year":"2017","journal-title":"Virology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e02192-23","DOI":"10.1128\/spectrum.02192-23","article-title":"Secreted NS1 Proteins of Tick-Borne Encephalitis Virus and West Nile Virus Block Dendritic Cell Activation and Effector Functions","volume":"11","author":"Gern","year":"2023","journal-title":"Microbiol. Spectr."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/11\/5311\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:44:41Z","timestamp":1760031881000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/11\/5311"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,31]]},"references-count":44,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["ijms26115311"],"URL":"https:\/\/doi.org\/10.3390\/ijms26115311","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,31]]}}}