This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shresta, S. Articles by Harris, E. Search for Related Content PubMed PubMed Citation Articles by Shresta, S. Articles by Harris, E.

Murine Model for Dengue Virus-Induced Lethal Disease with Increased Vascular Permeability

Sujan Shresta,^2* Kristin L. Sharar,^2, Daniil M. Prigozhin,^2, P. Robert Beatty,¹ and Eva Harris^1*

Division of Infectious Diseases, School of Public Health, 140 Warren Hall, University of California at Berkeley, Berkeley, California 94720-7360,¹ La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, California 92121²

Received 9 January 2006/ Accepted 31 July 2006

Lack of an appropriate animal model for dengue virus (DEN), which causes dengue fever and dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), has impeded characterization of the mechanisms underlying the disease pathogenesis. The cardinal feature of DHF/DSS, the severe form of DEN infection, is increased vascular permeability. To develop a murine model that is more relevant to DHF/DSS, a novel DEN strain, D2S10, was generated by alternately passaging a non-mouse-adapted DEN strain between mosquito cells and mice, thereby mimicking the natural transmission cycle of the virus between mosquitoes and humans. After infection with D2S10, mice lacking interferon receptors died early without manifesting signs of paralysis, carried infectious virus in both non-neuronal and neuronal tissues, and exhibited signs of increased vascular permeability. In contrast, mice infected with the parental DEN strain developed paralysis at late times after infection, contained detectable levels of virus only in the central nervous system, and displayed normal vascular permeability. In the mice infected with D2S10, but not the parental DEN strain, significant levels of serum tumor necrosis factor alpha (TNF-) were produced, and the neutralization of TNF- activity prevented early death of D2S10-infected mice. Sequence analysis comparing D2S10 to its parental strain implicated a conserved region of amino acid residues in the envelope protein as a possible source for the D2S10 phenotype. These results demonstrate that D2S10 causes a more relevant disease in mice and that TNF- may be one of several key mediators of severe DEN-induced disease in mice. This report represents a significant advance in animal models for severe DEN disease, and it begins to provide mechanistic insights into DEN-induced disease in vivo.

These authors contributed equally.

This article has been cited by other articles:

• Stein, D. A., Huang, C. Y.-H., Silengo, S., Amantana, A., Crumley, S., Blouch, R. E., Iversen, P. L., Kinney, R. M. (2008). Treatment of AG129 mice with antisense morpholino oligomers increases survival time following challenge with dengue 2 virus. J Antimicrob Chemother 0: dkn221v1-11 [Abstract] [Full Text]  
• Wati, S., Li, P., Burrell, C. J., Carr, J. M. (2007). Dengue Virus (DV) Replication in Monocyte-Derived Macrophages Is Not Affected by Tumor Necrosis Factor Alpha (TNF-{alpha}), and DV Infection Induces Altered Responsiveness to TNF-{alpha} Stimulation. J. Virol. 81: 10161-10171 [Abstract] [Full Text]  
• Sariol, C. A., Munoz-Jordan, J. L., Abel, K., Rosado, L. C., Pantoja, P., Giavedoni, L., Rodriguez, I. V., White, L. J., Martinez, M., Arana, T., Kraiselburd, E. N. (2007). Transcriptional Activation of Interferon-Stimulated Genes but Not of Cytokine Genes after Primary Infection of Rhesus Macaques with Dengue Virus Type 1. CVI 14: 756-766 [Abstract] [Full Text]  
• Chen, H.-C., Hofman, F. M., Kung, J. T., Lin, Y.-D., Wu-Hsieh, B. A. (2007). Both Virus and Tumor Necrosis Factor Alpha Are Critical for Endothelium Damage in a Mouse Model of Dengue Virus-Induced Hemorrhage. J. Virol. 81: 5518-5526 [Abstract] [Full Text]  
• Clyde, K., Kyle, J. L., Harris, E. (2006). Recent Advances in Deciphering Viral and Host Determinants of Dengue Virus Replication and Pathogenesis. J. Virol. 80: 11418-11431 [Full Text]