{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T20:10:18Z","timestamp":1793391018695,"version":"4.5.0"},"reference-count":43,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,1,13]],"date-time":"2022-01-13T00:00:00Z","timestamp":1642032000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP21fk0108114"],"award-info":[{"award-number":["JP21fk0108114"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP21fm0208101"],"award-info":[{"award-number":["JP21fm0208101"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","award":["60375406"],"award-info":[{"award-number":["60375406"]}],"id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Ebola virus disease (EVD) is a lethal disease caused by the highly pathogenic Ebola virus (EBOV), and its major symptoms in severe cases include vascular leakage and hemorrhage. These symptoms are caused by abnormal activation and disruption of endothelial cells (ECs) whose mediators include EBOV glycoprotein (GP) without the need for viral replication. However, the detailed molecular mechanisms underlying virus\u2013host interactions remain largely unknown. Here, we show that EBOV-like particles (VLPs) formed by GP, VP40, and NP activate ECs in a GP-dependent manner, as demonstrated by the upregulation of intercellular adhesion molecules-1 (ICAM-1) expression. VLPs-mediated ECs activation showed a different kinetic pattern from that of TNF-\u03b1-mediated activation and was associated with apoptotic ECs disruption. In contrast to TNF-\u03b1, VLPs induced ICAM-1 overexpression at late time points. Furthermore, screening of host cytoskeletal signaling inhibitors revealed that focal adhesion kinase inhibitors were found to be potent inhibitors of ICAM-1 expression mediated by both TNF-\u03b1 and VLPs. Our results suggest that EBOV GP stimulates ECs to induce endothelial activation and dysfunction with the involvement of host cytoskeletal signaling factors, which represent potential therapeutic targets for EVD.<\/jats:p>","DOI":"10.3390\/v14010142","type":"journal-article","created":{"date-parts":[[2022,1,14]],"date-time":"2022-01-14T03:14:56Z","timestamp":1642130096000},"page":"142","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Ebola Virus GP Activates Endothelial Cells via Host Cytoskeletal Signaling Factors"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1047-2189","authenticated-orcid":false,"given":"Benedicte Mpia","family":"Moni","sequence":"first","affiliation":[{"name":"Department of Emerging Infectious Diseases, Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan"},{"name":"Program for Nurturing Global Leaders in Tropical and Emerging Communicable Diseases, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523, Japan"},{"name":"Department of Virology, National Institute for Biomedical Research, Kinshasa, Democratic Republic of the Congo"},{"name":"Department of Biology, Faculty of Sciences, University of Kinshasa, Kinshasa, Democratic Republic of the Congo"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuteru","family":"Sakurai","sequence":"additional","affiliation":[{"name":"Department of Emerging Infectious Diseases, Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan"},{"name":"National Research Center for the Control and Prevention of Infectious Diseases, Nagasaki University, Nagasaki 852-8523, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9928-5621","authenticated-orcid":false,"given":"Jiro","family":"Yasuda","sequence":"additional","affiliation":[{"name":"Department of Emerging Infectious Diseases, Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan"},{"name":"Program for Nurturing Global Leaders in Tropical and Emerging Communicable Diseases, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523, Japan"},{"name":"National Research Center for the Control and Prevention of Infectious Diseases, Nagasaki University, Nagasaki 852-8523, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"10442","DOI":"10.1128\/JVI.79.16.10442-10450.2005","article-title":"Effects of Ebola virus glycoproteins on endothelial cell activation and barrier function","volume":"79","author":"Afanasieva","year":"2005","journal-title":"J. Virol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1038\/nri1154","article-title":"Ebola virus: From discovery to vaccine","volume":"3","author":"Feldmann","year":"2003","journal-title":"Nat. Rev. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1006\/viro.1998.9389","article-title":"The nonstructural small glycoprotein sGP of Ebola virus is secreted as an antiparallel-orientated homodimer","volume":"250","author":"Volchkova","year":"1998","journal-title":"Virology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1006\/viro.1995.0052","article-title":"GP mRNA of Ebola virus is edited by the Ebola virus polymerase and by T7 and vaccinia virus polymerases","volume":"214","author":"Volchkov","year":"1995","journal-title":"Virology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3602","DOI":"10.1073\/pnas.93.8.3602","article-title":"The virion glycoproteins of Ebola viruses are encoded in two reading frames and are expressed through transcriptional editing","volume":"93","author":"Sanchez","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Cook, J.D., and Lee, J.E. (2013). The secret life of viral entry glycoproteins: Moonlighting in immune evasion. PLoS Pathog., 9.","DOI":"10.1371\/journal.ppat.1003258"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Mehedi, M., Hoenen, T., Robertson, S., Ricklefs, S., Dolan, M.A., Taylor, T., Falzarano, D., Ebihara, H., Porcella, S.F., and Feldmann, H. (2013). Ebola Virus RNA Editing Depends on the Primary Editing Site Sequence and an Upstream Secondary Structure. PLoS Pathog., 9.","DOI":"10.1371\/journal.ppat.1003677"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1038\/cdd.2015.67","article-title":"Molecular mechanisms of Ebola virus pathogenesis: Focus on cell death","volume":"22","author":"Falasca","year":"2015","journal-title":"Cell Death Differ."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Escudero-P\u00e9rez, B., Volchkova, V.A., Dolnik, O., Lawrence, P., and Volchkov, V.E. (2014). Shed GP of Ebola virus triggers immune activation and increased vascular permeability. PLoS Pathog., 10.","DOI":"10.1371\/journal.ppat.1004509"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s12250-016-3850-1","article-title":"The roles of ebolavirus glycoproteins in viral pathogenesis","volume":"32","author":"Ning","year":"2017","journal-title":"Virol. Sin."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"34","DOI":"10.3389\/fmicb.2012.00034","article-title":"Filovirus tropism: Cellular molecules for viral entry","volume":"3","author":"Takada","year":"2012","journal-title":"Front. Microbiol."},{"key":"ref_12","unstructured":"Knipe, D.M., and Howley, P.M. (2013). Filoviridae: Marburg and Ebola viruses. Fields Virology, Lippincott Williams & Wilkins. [6th ed.]."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"100765","DOI":"10.1016\/j.isci.2019.100765","article-title":"Ebola hemorrhagic shock syndrome-on-a-chip","volume":"23","author":"Junaid","year":"2020","journal-title":"iScience"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2371","DOI":"10.1016\/S0002-9440(10)63592-4","article-title":"Pathogenesis of Ebola hemorrhagic fever in primate models","volume":"163","author":"Geisbert","year":"2003","journal-title":"Am. J. Pathol."},{"key":"ref_15","first-page":"159","article-title":"The glycoproteins of Marburg and Ebola virus and their potential roles in pathogenesis","volume":"15","author":"Feldmann","year":"1999","journal-title":"Arch. Virol. Suppl."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2839","DOI":"10.1099\/0022-1317-82-12-2839","article-title":"Biosynthesis and role of filoviral glycoproteins","volume":"82","author":"Feldmann","year":"2001","journal-title":"J. Gen. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1038\/78654","article-title":"Identification of the Ebola virus glycoprotein as the main viral determinant of vascular cell cytotoxicity and injury","volume":"6","author":"Yang","year":"2000","journal-title":"Nat. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1023\/A:1009657006550","article-title":"Apoptosis in fatal Ebola infection. Does the virus toll the bell for the immune system?","volume":"5","author":"Baize","year":"2000","journal-title":"Apoptosis"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2964","DOI":"10.4049\/jimmunol.162.5.2964","article-title":"Lymphocyte migration through brain endothelial cell monolayers involves signaling through endothelial ICAM-1 via a rho-dependent pathway","volume":"162","author":"Adamson","year":"1999","journal-title":"J. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/S1537-1891(03)00008-9","article-title":"Rho GTPases and the regulation of endothelial permeability","volume":"39","author":"Ridley","year":"2002","journal-title":"Vasc. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1038\/sj.jid.5700670","article-title":"Increased ICAM-1 expression causes endothelial cell leakiness, cytoskeletal reorganization, and junctional alterations","volume":"127","author":"Clark","year":"2007","journal-title":"J. Investig. Dermatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e985954","DOI":"10.4161\/21688370.2014.985954","article-title":"Control of vascular permeability by adhesion molecules","volume":"3","author":"Sarelius","year":"2015","journal-title":"Tissue Barriers"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1161\/01.RES.0000210579.35304.d3","article-title":"Rho GTPases and leukocyte adhesion receptor expression and function in endothelial cells","volume":"98","author":"Ridley","year":"2006","journal-title":"Circ. Res."},{"key":"ref_24","first-page":"112","article-title":"Fasudil attenuates lipopolysaccharide-induced acute lung injury in mice through the Rho\/Rho kinase pathway","volume":"16","author":"Li","year":"2010","journal-title":"Med. Sci. Monit."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1165\/rcmb.2004-0009OC","article-title":"Attenuation of endotoxin-induced acute lung injury by the Rho associated kinase inhibitor, Y-27632","volume":"32","author":"Tasaka","year":"2005","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"8720","DOI":"10.1128\/JVI.01239-16","article-title":"An Ebola virus-like particle-based reporter system enables evaluation of antiviral drugs in vivo under non-biosafety level 4 conditions","volume":"90","author":"Li","year":"2016","journal-title":"J. Virol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2324","DOI":"10.1128\/JVI.75.5.2324-2330.2001","article-title":"Infectivity-Enhancing Antibodies to Ebola Virus Glycoprotein","volume":"75","author":"Takada","year":"2001","journal-title":"J Virol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"9987","DOI":"10.1128\/JVI.77.18.9987-9992.2003","article-title":"Nedd4 regulates egress of Ebola virus-like particles from host cells","volume":"77","author":"Yasuda","year":"2003","journal-title":"J. Virol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Nanbo, A., Imai, M., Watanabe, S., Noda, T., Takahash, K., Neumann, G., Halfmann, P., and Kawaoka, Y. (2010). Ebolavirus is internalized into host cells via macropinocytosis in a viral glycoprotein-dependent manner. PLoS Pathog., 6.","DOI":"10.1371\/journal.ppat.1001121"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Saeed, M.F., Kolokoltsov, A.A., Albrecht, T., and Davey, R.A. (2010). Cellular Entry of Ebola Virus Involves Uptake by a Macropinocytosis-Like Mechanism and Subsequent Trafficking through Early and Late Endosomes. PLoS Pathog., 6.","DOI":"10.1371\/journal.ppat.1001110"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"67","DOI":"10.4161\/cam.28244","article-title":"Rho-GTPase signaling in leukocyte extravasation: An endothelial point of view","volume":"8","author":"Heemskerk","year":"2014","journal-title":"Cell Adh. Migr."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1002\/cm.20472","article-title":"Rho-kinase\/ROCK: A key regulator of the cytoskeleton and cell polarity","volume":"67","author":"Amano","year":"2010","journal-title":"Cytoskeleton"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"10029","DOI":"10.1038\/ncomms10029","article-title":"A molecular ruler regulates cytoskeletal remodeling by the Rho kinases","volume":"6","author":"Truebestein","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1965","DOI":"10.1126\/science.1057269","article-title":"Recovery of infectious Ebola virus from complementary DNA: RNA editing of the GP gene and viral cytotoxicity","volume":"291","author":"Volchkov","year":"2001","journal-title":"Science"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.virol.2003.12.014","article-title":"Ebola virus glycoprotein-mediated anoikis of primary human cardiac microvascular endothelial cells","volume":"321","author":"Ray","year":"2004","journal-title":"Virology"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Faye, O., Andronico, A., Faye, O., Salje, H., Bo\u00eblle, P.Y., Magassouba, N., Bah, E.I., Koivogui, L., Diallo, B., and Diallo, A.A. (2015). Use of viremia to evaluate the baseline case fatality ratio of Ebola virus disease and inform treatment studies: A retrospective cohort study. PLoS Med., 12.","DOI":"10.1371\/journal.pmed.1001908"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1002\/jlb.66.6.876","article-title":"Regulation of intercellular adhesion molecule-1 (CD54) gene expression","volume":"66","author":"Roebuck","year":"1999","journal-title":"J. Leukoc. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"7766","DOI":"10.1128\/JVI.02469-10","article-title":"Crimean. Crimean-Congo hemorrhagic fever virus activates endothelial cells","volume":"85","author":"Moll","year":"2011","journal-title":"J. Virol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"214074","DOI":"10.1155\/2010\/214074","article-title":"Cellular stress responses: Cell survival and cell death","volume":"2010","author":"Fulda","year":"2010","journal-title":"Int. J. Cell Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1002\/jcp.20991","article-title":"Hic-5 Contributes to epithelial-mesenchymal transformation through a RhoA\/ROCK-dependent pathway","volume":"211","author":"Tumbarello","year":"2007","journal-title":"J. Cell Physiol."},{"key":"ref_41","first-page":"e90","article-title":"Crosstalk between reticular adherens junctions and platelet endothelial cell adhesion molecule-1 regulates endothelial barrier function","volume":"32","author":"Bigarella","year":"2012","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1160\/th14-04-0299","article-title":"TNF-induced endothelial barrier disruption: Beyond actin and Rho","volume":"112","year":"2014","journal-title":"Thromb. Haemost."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1080\/15384047.2017.1416937","article-title":"Focal adhesion kinase a potential therapeutic target for pancreatic cancer and malignant pleural mesothelioma","volume":"19","author":"Kanteti","year":"2018","journal-title":"Cancer Biol. Ther."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/1\/142\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:02:19Z","timestamp":1760364139000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/1\/142"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,13]]},"references-count":43,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["v14010142"],"URL":"https:\/\/doi.org\/10.3390\/v14010142","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,13]]}}}