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Journal of Virology, December 2008, p. 12312-12324, Vol. 82, No. 24
0022-538X/08/$08.00+0     doi:10.1128/JVI.00968-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Enhancement by Tumor Necrosis Factor Alpha of Dengue Virus-Induced Endothelial Cell Production of Reactive Nitrogen and Oxygen Species Is Key to Hemorrhage Development{triangledown}

Yu-Ting Yen,1 Hseun-Chin Chen,1 Yang-Ding Lin,1 Chi-Chang Shieh,2,3 and Betty A. Wu-Hsieh1,3*

Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan,1 Departments of Microbiology and Immunology and Pediatrics, National Cheng Kung University Medical College, Tainan, Taiwan,2 Division of Clinical Research, National Health Research Institute, Tainan, Taiwan3

Received 9 May 2008/ Accepted 28 August 2008

Hemorrhage is a severe manifestation of dengue disease. Virus strain and host immune response have been implicated as the risk factors for hemorrhage development. To delineate the complex interplay between the virus and the host, we established a dengue hemorrhage model in immune-competent mice. Mice inoculated intradermally with dengue virus develop hemorrhage within 3 days. In the present study, we showed by the presence of NS1 antigen and viral nuclei acid that dengue virus actively infects the endothelium at 12 h and 24 h after inoculation. Temporal studies showed that beginning at day 2, there was macrophage infiltration into the vicinity of the endothelium, increased tumor necrosis factor alpha (TNF-{alpha}) production, and endothelial cell apoptosis in the tissues. In the meantime, endothelial cells in the hemorrhage tissues expressed inducible nitric oxide synthase (iNOS) and nitrotyrosine. In vitro studies showed that primary mouse and human endothelial cells were productively infected by dengue virus. Infection by dengue virus induced endothelial cell production of reactive nitrogen and oxygen species and apoptotic cell death, which was greatly enhanced by TNF-{alpha}. NG-Nitro-L-arginine methyl ester and N-acetyl cysteine reversed the effects of dengue virus and TNF-{alpha} on endothelial cells. Importantly, hemorrhage development and the severity of hemorrhage were greatly reduced in mice lacking iNOS or p47phox or treatment with oxidase inhibitor, pointing to the critical roles of reactive nitrogen and oxygen species in dengue hemorrhage.

* Corresponding author. Mailing address: Graduate Institute of Immunology, National Taiwan University College of Medicine, No. 1 Jen-Ai Road, Section 1, Taipei, Taiwan. Phone: 886-2-2321-7510. Fax: 886-2-2321-7921. E-mail: bwh{at}ntu.edu.tw

{triangledown} Published ahead of print on 8 October 2008.

Journal of Virology, December 2008, p. 12312-12324, Vol. 82, No. 24
0022-538X/08/$08.00+0     doi:10.1128/JVI.00968-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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