A mouse-passaged dengue virus strain with reduced affinity for heparan sulfate causes severe disease in mice by establishing increased systemic viral loads
A mouse-passaged dengue virus strain with reduced affinity for heparan sulfate causes severe disease in mice by establishing increased systemic viral loads
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DOI：
10.1128/jvi.00611-08
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发表时间：
2008-09-01
影响因子：
5.4
通讯作者：
Shresta, Sujan
中科院分区：
文献类型：
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作者：
Prestwood, Tyler R.;Prigozhin, Daniil M.;Shresta, Sujan
登革热病毒的四种血清型（DENV1 至 DENV4）可导致广泛的发病率和死亡率。研究疾病发病机制和开发治疗方法的一个主要障碍是缺乏小动物模型。我们之前报道过分离出一种 DENV2 毒株，该毒株是通过在蚊子细胞和小鼠之间传代临床分离株而获得的，该毒株在小鼠中引起严重的 DENV 疾病，并含有多种突变，包括包膜 (E) 蛋白的结构域 11 中的许多突变。在这里，我们描述了一种重组病毒，与非小鼠传代的病毒不同，E蛋白有两个突变，它会诱导血管渗漏和肿瘤坏死因子α（TNF-α）介导的致死性，而非小鼠传代的病毒会导致麻痹。这种重组病毒对硫酸乙酰肝素的亲和力较弱，导致感染小鼠血清半衰期延长、全身病毒载量增加以及血清中TNF-α水平升高。这些结果例证了E蛋白在调节病毒颗粒清除中的作用，并将清除对导致严重疾病表现的全身病毒载量的影响联系起来。
The four serotypes of dengue virus (DENV1 to DENV4) cause extensive morbidity and mortality. A major obstacle to studying disease pathogenesis and developing therapies has been the lack of a small-animal model. We previously reported isolation of a DENV2 strain, obtained by passaging a clinical isolate between mosquito cells and mice, that caused severe DENV disease in mice and contained multiple mutations, including many in domain 11 of the envelope (E) protein. Here, we describe a recombinant virus, differing from the non-mouse-passaged virus by two mutations in the E protein, that induces vascular leakage and tumor necrosis factor alpha (TNF-alpha) -mediated lethality, while the non-mouse-passaged virus causes paralysis. This recombinant virus has a weaker affinity for heparan sulfate, resulting in an increased serum half-life, higher systemic viral loads, and high levels of TNF-alpha in the serum of infected mice. These results exemplify the role of the E protein in modulating virion clearance and connect the effect of clearance on the systemic viral loads responsible for severe disease manifestations.