https://scholars.lib.ntu.edu.tw/handle/123456789/328954
標題: | Both virus and tumor necrosis factor alpha are critical for endothelium damage in a mouse model of dengue virus-induced hemorrhage | 作者: | Chen, H. C. Tai, CM BETTY AN-YE WU-HSIEH Hofman, F. M. Tu, CH Kung, J. T. Wu, HB Lin, Y. D. Perng, DS Lee, TC Wu-Hsieh, B. A. Shun, CT Wang, HP. |
公開日期: | 2007 | 卷: | 81 | 期: | 11 | 起(迄)頁: | 5518-5526 | 來源出版物: | Journal of Virology | 摘要: | 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-α) 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-α in tissues correlated with endothelial cell apoptosis and hemorrhage. By comparing TNF-α-/- to IgH-/-, C5 -/-, and wild-type mice, we found that TNF-α was important for the development of hemorrhage. In vitro studies showed that mouse primary microvascular endothelial cells were susceptible to DV but that TNF-α enhanced DV-induced apoptosis. Our mouse model illustrated that intradermal inoculation of high titers of DV predisposes endothelial cells to be susceptible to TNF-α-induced cell death, which leads to endothelium damage and hemorrhage development. This finding highlights the contribution of the innate immune response to dengue hemorrhage. Copyright ? 2007, American Society for Microbiology. All Rights Reserved. |
URI: | http://www.scopus.com/inward/record.url?eid=2-s2.0-34249823370&partnerID=MN8TOARS http://scholars.lib.ntu.edu.tw/handle/123456789/328954 |
DOI: | 10.1128/JVI.02575-06 | SDG/關鍵字: | complement component C5 inhibitor; immunoglobulin heavy chain; tumor necrosis factor alpha; animal cell; animal experiment; animal model; apoptosis; article; bleeding; C57BL 6 mouse; cell infiltration; controlled study; cytokine production; dengue; Dengue virus; disease model; endothelium lesion; immunofluorescence; innate immunity; macrophage; mouse; nonhuman; priority journal; serotype; staining; thrombocytopenia; virus load; virus strain; Animals; Apoptosis; Dengue Hemorrhagic Fever; Dengue Virus; Disease Models, Animal; Endothelium, Vascular; Mice; Mice, Inbred A; Mice, Inbred C57BL; Mice, Knockout; Tumor Necrosis Factor-alpha; Dengue virus; Mus |
顯示於: | 免疫學研究所 |
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