DataSheet_1_Tree Shrew as a New Animal Model for the Study of Dengue Virus.doc

Dengue virus is a significant public health threat worldwide; however, the pathogenesis of dengue disease remains poorly understood due to lack of appropriate small animal models. Tree shrews are an emerging experimental animal model for the study of human diseases due to their resemblance of genetic characteristics to primate animals. Herein we report that dengue infection in tree shrews elicits resemble clinical symptoms as in humans. Dengue fever (△2°C> normal body temperature) developed in ~22% healthy Chinese tree shrews from 2 through 33 days after infection with a low dose (1 ∗ 104 PFU/animal) of dengue virus serotype 2 or 3 intravenously or subcutaneously. The dengue genomic RNA and neutralizing antibodies were detected in ~78% of animals at days 7 and 15 post infection respectively. The serum levels of liver enzymes including aspartate transaminase, alanine aminotransferase and alkaline phosphatase were elevated with peaks at day 7 after infection. Modest thrombocytopenia and a slight decrease in the white blood cell count were observed. Intriguingly, although viral RNA was barely detectable in the liver by 48 days after infection, it was still evident in the brain. The intra-brain bleeding lesions in the intravenous infection group were more severe than those in the subcutaneous infection group. Our data demonstrate that primary dengue virus infection in tree shrews causes resemble clinical disease as in humans and thus tree shrews may be a suitable model for the study of dengue disease pathogenesis.

登革病毒（Dengue virus）是全球范围内严重的公共卫生威胁；然而由于缺乏合适的小型动物模型，登革疾病的发病机制仍未得到充分阐释。树鼩（tree shrews）因其遗传特征与灵长类动物高度相似，正逐渐成为人类疾病研究的新兴实验动物模型。本研究报道，树鼩感染登革病毒后可出现与人类相似的临床症状：对约22%的健康中国树鼩，经静脉或皮下接种低剂量（1×10⁴ PFU/只）的登革病毒血清型2或3型后，在感染后2至33天出现登革热症状（体温较正常升高≥2℃）。分别在感染后第7天和第15天，约78%的动物体内可检测到登革病毒基因组RNA与中和抗体。感染后第7天，血清中天冬氨酸转氨酶、丙氨酸转氨酶及碱性磷酸酶等肝酶水平升至峰值并显著升高。同时观察到轻度血小板减少症与白细胞计数轻微下降的现象。值得关注的是，尽管感染后48天肝脏中几乎无法检测到病毒RNA，但脑组织中仍可检出病毒核酸。静脉接种组的脑内出血病变较皮下接种组更为严重。本研究数据表明，树鼩的原发性登革病毒感染可诱发与人类相似的临床疾病，因此树鼩或可成为研究登革疾病发病机制的适宜动物模型。