Appearance of renal hemorrhage in adult mice after inoculation of patient-derived hantavirus.
Appearance of renal hemorrhage in adult mice after inoculation of patient-derived hantavirus.
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接种患者衍生的汉塔病毒后，成年小鼠肾脏出血的出现。
DOI：
10.1186/s12985-017-0686-8
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发表时间：
2017-01-26
期刊：
影响因子：
4.8
通讯作者：
Arikawa J
中科院分区：
文献类型：
--
作者：
Shimizu K;Koma T;Yoshimatsu K;Tsuda Y;Isegawa Y;Arikawa J
肾综合征出血热（Hemorrhagic Fever with Renal Syndrome，HFRS）是由汉坦病毒（Hantavirus）感染引起的一种以发热、肾功能不全和出血为特征的疾病。模拟HFRS症状的动物模型尚待建立。在这项研究中，我们评估了肾综合征出血热患者源性汉滩病毒（HTNV）在成年小鼠中的致病性。用噬斑克隆法从肾综合征出血热（HFRS）患者血中分离到5株汉滩病毒（HTNV）KHF 83-61 BL株（KHFV）。用6周龄雌性BALB/c小鼠评价病毒克隆的致病性。通过常规方法进行病毒基因组的序列分析。所有经静脉接种KHFV克隆（cl）-1、-2、-3和-5的小鼠在接种后（dpi）6至9天均表现出疾病体征，如短暂的体重减轻、皮毛起皱、活动减少和肾髓质中显著突出的出血，然后恢复。相反，静脉接种KHFV cl-4的小鼠未显示任何疾病迹象。我们选择KHFV cl-5和cl-4分别作为高致病性和低致病性克隆的代表。KHFVcl-5感染小鼠肾组织中病毒RNA的量在感染后3、6、9和12天均大于KHFVcl-4感染小鼠。KHFV cl-5和cl-4病毒RNA含量在感染后3d达到高峰，即发病前。序列分析表明，在位置417的氨基酸在糖蛋白Gn是唯一的差异，在病毒蛋白之间的KHFV cl-5和cl-4。结果表明，KHFV cl-5和cl-4的致病性差异与Gn的417位氨基酸有关。当KHFV cl-5的接种物用抗HTNV毒株76-118（其属于与KHFV克隆相同的血清型）的中和抗体预处理时，小鼠没有显示出任何疾病迹象，证实该疾病是由KHFV感染引起的。我们发现，HFRS患者来源的HTNV引起成年小鼠肾出血。我们预期，这种感染模型将是一个有价值的工具，了解HFRS的发病机制。
Hemorrhagic fever with renal syndrome (HFRS) caused by hantavirus infection is characterized by fever, renal dysfunction and hemorrhage. An animal model mimicking symptoms of HFRS remains to be established. In this study, we evaluated the pathogenicity of an HFRS patient-derived Hantaan virus (HTNV) in adult mice. Five clones of HTNV strain KHF 83-61 BL (KHFV) that was derived from blood of an HFRS patient were obtained by plaque cloning. The pathogenicity of the virus clones was evaluated by using 6-week-old female BALB/c mice. Sequence analysis of the viral genome was performed by conventional methods. All of the mice intravenously inoculated with KHFV clone (cl)-1, -2, -3 and -5 showed signs of disease such as transient body weight loss, ruffled fur, reduced activity and remarkably prominent hemorrhage in the renal medulla at 6 to 9 days post-inoculation (dpi) and then recovered. In contrast, mice intravenously inoculated with KHFV cl-4 did not show any signs of disease. We selected KHFV cl-5 and cl-4 as representative of high-pathogenic and low-pathogenic clones, respectively. Quantities of viral RNA in kidneys of KHFV cl-5-infected mice were larger than those in KHFV cl-4-infected mice at any time point examined (3, 6, 9 and 12 dpi). The quantities of viral RNA of KHFV cl-5 and cl-4 peaked at 3 dpi, which was before the onset of disease. Sequence analysis revealed that the amino acid at position 417 in the glycoprotein Gn was the sole difference in viral proteins between KHFV cl-5 and cl-4. The result suggests that amino acid at position 417 in Gn is related to the difference in pathogenicity between KHFV cl-5 and cl-4. When the inoculum of KHFV cl-5 was pretreated with a neutralizing antibody against HTNV strain 76-118, which belongs to the same serotype as KHFV clones, mice did not show any signs of disease, confirming that the disease was caused by KHFV infection. We found that an HFRS patient-derived HTNV caused renal hemorrhage in adult mice. We anticipate that this infection model will be a valuable tool for understanding the pathogenesis of HFRS.