{"title":"Dengue Envelope Protein as a Cytotoxic Factor Inducing Hemorrhage and Endothelial Cell Death in Mice.","authors":"Te-Sheng Lien, Der-Shan Sun, Wen-Sheng Wu, Hsin-Hou Chang","doi":"10.3390/ijms251910858","DOIUrl":null,"url":null,"abstract":"<p><p>Dengue virus (DENV) infection, prevalent in tropical and subtropical regions, can progress to dengue hemorrhagic fever (DHF), which increases mortality during secondary infections. DHF is characterized by endothelial damage and vascular leakage. Despite its severity, no specific antiviral treatments exist, and the viral factors responsible for endothelial damage remain unclear. This study examines the role of the DENV envelope protein domain III (EIII) in inducing endothelial apoptosis using a mouse model. Additionally, we aim to explore whether cell death-inducing pathways could serve as drug targets to ameliorate EIII-induced endothelial injury and hemorrhage. In vitro experiments using human endothelial HMEC-1 cells demonstrated that both recombinant EIII (rEIII) and DENV markedly induced caspase-3-mediated endothelial cell death, an effect that was attenuated by co-treatment with chondroitin sulfate B (CSB), N-acetyl cysteine (NAC), and the caspase-3 inhibitor z-DEVD-FMK. In vivo, sequential injections of rEIII and anti-platelet immunoglobulin in mice, designed to mimic the clinical phase of DHF with peak viremia followed by an increase in DENV-induced Ig, including autoantibodies, revealed that these dual treatments markedly triggered caspase-3-dependent apoptosis in vascular endothelial cells at hemorrhage sites. Treatments with z-DEVD-FMK effectively reduced DHF-like symptoms such as thrombocytopenia, hemorrhage, inflammation, hypercoagulation, and endothelial damage. Additionally, CSB and NAC alleviated hemorrhagic symptoms in the mice. These results suggest that targeting EIII, reactive oxygen species, and caspase-3-mediated apoptosis could offer potential therapeutic strategies for addressing EIII-induced hemorrhagic pathogenesis.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":5.6000,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11476790/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Molecular Sciences","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.3390/ijms251910858","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
Abstract
Dengue virus (DENV) infection, prevalent in tropical and subtropical regions, can progress to dengue hemorrhagic fever (DHF), which increases mortality during secondary infections. DHF is characterized by endothelial damage and vascular leakage. Despite its severity, no specific antiviral treatments exist, and the viral factors responsible for endothelial damage remain unclear. This study examines the role of the DENV envelope protein domain III (EIII) in inducing endothelial apoptosis using a mouse model. Additionally, we aim to explore whether cell death-inducing pathways could serve as drug targets to ameliorate EIII-induced endothelial injury and hemorrhage. In vitro experiments using human endothelial HMEC-1 cells demonstrated that both recombinant EIII (rEIII) and DENV markedly induced caspase-3-mediated endothelial cell death, an effect that was attenuated by co-treatment with chondroitin sulfate B (CSB), N-acetyl cysteine (NAC), and the caspase-3 inhibitor z-DEVD-FMK. In vivo, sequential injections of rEIII and anti-platelet immunoglobulin in mice, designed to mimic the clinical phase of DHF with peak viremia followed by an increase in DENV-induced Ig, including autoantibodies, revealed that these dual treatments markedly triggered caspase-3-dependent apoptosis in vascular endothelial cells at hemorrhage sites. Treatments with z-DEVD-FMK effectively reduced DHF-like symptoms such as thrombocytopenia, hemorrhage, inflammation, hypercoagulation, and endothelial damage. Additionally, CSB and NAC alleviated hemorrhagic symptoms in the mice. These results suggest that targeting EIII, reactive oxygen species, and caspase-3-mediated apoptosis could offer potential therapeutic strategies for addressing EIII-induced hemorrhagic pathogenesis.
期刊介绍:
The International Journal of Molecular Sciences (ISSN 1422-0067) provides an advanced forum for chemistry, molecular physics (chemical physics and physical chemistry) and molecular biology. It publishes research articles, reviews, communications and short notes. Our aim is to encourage scientists to publish their theoretical and experimental results in as much detail as possible. Therefore, there is no restriction on the length of the papers or the number of electronics supplementary files. For articles with computational results, the full experimental details must be provided so that the results can be reproduced. Electronic files regarding the full details of the calculation and experimental procedure, if unable to be published in a normal way, can be deposited as supplementary material (including animated pictures, videos, interactive Excel sheets, software executables and others).