Murine model for dengue virus-induced lethal disease with increased vascular permeability
Murine model for dengue virus-induced lethal disease with increased vascular permeability
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DOI：
10.1128/jvi.00062-06
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发表时间：
2006-10-01
影响因子：
5.4
通讯作者：
Harris, Eva
中科院分区：
文献类型：
--
作者：
Shresta, Sujan;Sharar, Kristin L.;Harris, Eva
登革病毒（DEN）可引起登革热和登革出血热/登革休克综合征（DHF/DSS），由于缺乏合适的登革病毒动物模型，阻碍了登革病毒发病机制的研究。DHF/DSS是DEN感染的严重形式，其主要特征是血管通透性增加。为了开发与DHF/DSS更相关的鼠模型，通过在蚊子细胞和小鼠之间交替传代非小鼠适应的DEN株，从而模拟病毒在蚊子和人之间的自然传播周期，产生了新的DEN株D2 S10。在用D2 S10感染后，缺乏干扰素受体的小鼠早期死亡，没有表现出瘫痪的迹象，在非神经元和神经元组织中携带感染性病毒，并表现出血管通透性增加的迹象。相比之下，感染亲本DEN菌株的小鼠在感染后晚期出现瘫痪，仅在中枢神经系统中含有可检测水平的病毒，并显示正常的血管通透性。在感染D2 S10而非亲代DEN菌株的小鼠中，产生了显著水平的血清肿瘤坏死因子α（TNF-α），并且TNF-α活性的中和防止了D2 S10感染小鼠的早期死亡。比较D2 S10与其亲本菌株的序列分析表明，包膜蛋白中的氨基酸残基保守区可能是D2 S10表型的来源。这些结果表明，D2 S10在小鼠中引起更相关的疾病，并且TNF-α可能是小鼠中严重DEN诱导的疾病的几种关键介质之一。该报告代表了严重DEN疾病动物模型的重大进展，并开始提供体内DEN诱导疾病的机制见解。
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-alpha) were produced, and the neutralization of TNF-alpha 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-alpha 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.