Humanized Mice Show Clinical Signs of Dengue Fever according to Infecting Virus Genotype
Humanized Mice Show Clinical Signs of Dengue Fever according to Infecting Virus Genotype
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DOI：
10.1128/jvi.00581-09
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发表时间：
2009-09-01
影响因子：
5.4
通讯作者：
Rico-Hesse, Rebeca
中科院分区：
文献类型：
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作者：
Mota, Javier;Rico-Hesse, Rebeca
我们证明，感染不同菌株（代表四种基因型）登革热病毒血清2型（DEN-2）的人源化NOD-scid IL2r γ (null)小鼠可诱导发生类似人的疾病，包括发热、病毒血症、红斑和血小板减少症。新生小鼠经辐照后接受肝内接种人脐带血来源的造血祖细胞（CD34(+)）的移植。6周后，用流式细胞术检测小鼠外周血中人淋巴细胞（CD45（+）细胞）的水平；重建率从16%到80%不等（中位数为52%）。感染8种低传代数菌株的人源化小鼠（大约10(6)PFU，相当于蚊子叮咬）在感染后12至18天产生高病毒血症。我们观察到，与仅接种细胞培养基的人源化小鼠相比，大多数小鼠在第10天血小板显著减少，体温（发烧）和红斑（皮疹）升高。在该模型中，东南亚（SE）亚洲病毒与其他基因型病毒（美洲、印度和西非）在病毒血症和皮疹的程度和持续时间上存在显著差异，其中东南亚病毒总是最高的。与其他病毒相比，印度基因型病毒产生较低的病毒血症和较少的血小板减少症，西非（森林）病毒产生最短的病毒血症期和最低的皮疹测量值。这些结果与先前描述的主要人类靶细胞和整只蚊子的毒力和传播差异有关，并可能与世界各地的流行病学观察结果有关。这些特点使该小鼠模型成为研究登革热发病机制和评估疫苗衰减和抗病毒药物的理想模型。
We demonstrated that the infection of humanized NOD-scid IL2r gamma(null) mice with different strains (representing the four genotypes) of dengue virus serotype 2 (DEN-2) can induce the development of human-like disease, including fever, viremia, erythema, and thrombocytopenia. Newborn mice were irradiated and received transplants by intrahepatic inoculation of human cord blood-derived hematopoietic progenitor cells (CD34(+)). After 6 weeks, mouse peripheral blood was tested by flow cytometry to determine levels of human lymphocytes (CD45(+) cells); rates of reconstitution ranged from 16 to 80% (median, 52%). Infection (with approximately 10(6) PFU, the equivalent of a mosquito bite) of these humanized mice with eight low-passage-number strains produced a high viremia extending to days 12 to 18 postinfection. We observed a significant decrease in platelets at day 10 in most of the mice and an increase in body temperature (fever) and erythema (rash) in comparison with humanized mice inoculated with cell culture medium only. Comparison of Southeast (SE) Asian and other genotype viruses (American, Indian, and West African) in this model showed significant differences in magnitude and duration of viremia and rash, with the SE Asian viruses always being highest. Indian genotype viruses produced lower viremias and less thrombocytopenia than the others, and West African (sylvatic) viruses produced the shortest periods of viremia and the lowest rash measurements. These results correlate with virulence and transmission differences described previously for primary human target cells and whole mosquitoes and may correlate with epidemiologic observations around the world. These characteristics make this mouse model ideal for the study of dengue pathogenesis and the evaluation of vaccine attenuation and antivirals.