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Journal of Virology, June 2007, p. 5518-5526, Vol. 81, No. 11
0022-538X/07/$08.00+0     doi:10.1128/JVI.02575-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Both Virus and Tumor Necrosis Factor Alpha Are Critical for Endothelium Damage in a Mouse Model of Dengue Virus-Induced Hemorrhage{triangledown}

Hsuen-Chin Chen,1 Florence M. Hofman,2 John T. Kung,3 Yang-Ding Lin,1 and Betty A. Wu-Hsieh1*

Graduate Institute of Immunology, National Taiwan University, College of Medicine, Taipei, Taiwan, Republic of China,1 Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California,2 Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan, Republic of China3

Received 22 November 2006/ Accepted 7 March 2007

Hemorrhage is a common clinical manifestation in dengue patients. However, the pathogenic mechanism of dengue virus (DV)-induced hemorrhage awaits clarification. We established a mouse model of DV hemorrhage using immunocompetent C57BL/6 mice by injecting DV serotype 2 strain 16681 intradermally. While inoculation of 3 x 109 PFU of DV induced systemic hemorrhage in all of the mice by day 3 of infection, one out of three of those injected with 4 x 107 to 8 x 107 PFU developed hemorrhage in the subcutaneous tissues. The mice that were inoculated with 4 x 107 to 8 x 107 PFU but that did not develop hemorrhage were used as a basis for comparison to explore the pathogenic mechanism of dengue hemorrhage. The results showed that mice with severe thrombocytopenia manifested signs of vascular leakage and hemorrhage. We observed that high viral titer, macrophage infiltration, and tumor necrosis factor alpha (TNF-{alpha}) production in the local tissues are three important events that lead to hemorrhage. Immunofluorescence staining revealed that DV targeted both endothelial cells and macrophages. In addition, the production of high levels of TNF-{alpha} in tissues correlated with endothelial cell apoptosis and hemorrhage. By comparing TNF-{alpha}–/– to IgH–/–, C5–/–, and wild-type mice, we found that TNF-{alpha} was important for the development of hemorrhage. In vitro studies showed that mouse primary microvascular endothelial cells were susceptible to DV but that TNF-{alpha} enhanced DV-induced apoptosis. Our mouse model illustrated that intradermal inoculation of high titers of DV predisposes endothelial cells to be susceptible to TNF-{alpha}-induced cell death, which leads to endothelium damage and hemorrhage development. This finding highlights the contribution of the innate immune response to dengue hemorrhage.

* Corresponding author. Mailing address: Graduate Institute of Immunology, National Taiwan University College of Medicine, No. 1 Jen-Ai Road, Section 1, Taipei 10051, Taiwan, Republic of China. Phone: 886 2 23217510. Fax: 886 2 23217921. E-mail: wuhsiehb{at}ha.mc.ntu.edu.tw

{triangledown} Published ahead of print on 14 March 2007.

Journal of Virology, June 2007, p. 5518-5526, Vol. 81, No. 11
0022-538X/07/$08.00+0     doi:10.1128/JVI.02575-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Cheng, H.-J., Lin, C.-F., Lei, H.-Y., Liu, H.-S., Yeh, T.-M., Luo, Y.-H., Lin, Y.-S. (2009). Proteomic Analysis of Endothelial Cell Autoantigens Recognized by Anti-Dengue Virus Nonstructural Protein 1 Antibodies. Exp. Biol. Med. 234: 63-73 [Abstract] [Full Text]  
  • Yen, Y.-T., Chen, H.-C., Lin, Y.-D., Shieh, C.-C., Wu-Hsieh, B. A. (2008). Enhancement by Tumor Necrosis Factor Alpha of Dengue Virus-Induced Endothelial Cell Production of Reactive Nitrogen and Oxygen Species Is Key to Hemorrhage Development. J. Virol. 82: 12312-12324 [Abstract] [Full Text]  
  • Shrestha, B., Zhang, B., Purtha, W. E., Klein, R. S., Diamond, M. S. (2008). Tumor Necrosis Factor Alpha Protects against Lethal West Nile Virus Infection by Promoting Trafficking of Mononuclear Leukocytes into the Central Nervous System. J. Virol. 82: 8956-8964 [Abstract] [Full Text]  


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