Modeling the Disease Course of Zaire ebolavirus Infection in the Outbred Guinea Pig
Modeling the Disease Course of Zaire ebolavirus Infection in the Outbred Guinea Pig
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DOI：
10.1093/infdis/jiv237
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发表时间：
2015-10-01
影响因子：
6.4
通讯作者：
Geisbert, Thomas W.
中科院分区：
文献类型：
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作者：
Cross, Robert W.;Fenton, Karla A.;Geisbert, Thomas W.
背景需要准确反映人类丝状病毒感染的啮齿动物模型作为医学对策的早期筛选。先前在扎伊尔种埃博拉病毒（ZEBOV）啮齿动物中的工作主要使用近交系小鼠和豚鼠来模拟疾病。然而，这些近交物种不显示灵长类动物ZEBOV感染的一些重要特征，最显著的是凝血异常。36只远交系豚鼠感染豚鼠适应的ZEBOV，并在8天内连续检查，以研究导致死亡的病理事件。ZEBOV感染的远系豚鼠的疾病特征与人类和非人灵长类动物的疾病特征基本一致，包括巨噬细胞和树突状细胞的早期感染、旁观者淋巴细胞的凋亡以及促炎细胞因子水平的增加。最重要的是，纤维蛋白原、蛋白C活性和抗纤溶蛋白的循环水平失调以及组织中纤维蛋白的沉积均证明了弥散性血管内凝血的生化和显微镜证据。这些发现表明，远交豚鼠模型比近交啮齿动物模型更好地再现了灵长类动物的ZEBOV感染，可用于剖析ZEBOV发病机制中的关键事件，并且可用于在灵长类动物中评估之前评估候选干预措施。
Background. Rodent models that accurately reflect human filovirus infection are needed as early screens for medical countermeasures. Prior work in rodents with the Zaire species of Ebola virus (ZEBOV) primarily used inbred mice and guinea pigs to model disease. However, these inbred species do not show some of the important features of primate ZEBOV infection, most notably, coagulation abnormalities.Methods. Thirty-six outbred guinea pigs were infected with guinea pig-adapted ZEBOV and examined sequentially over an 8-day period to investigate the pathologic events that lead to death.Results. Features of disease in ZEBOV-infected outbred guinea pigs were largely consistent with disease in humans and nonhuman primates and included early infection of macrophages and dendritiform cells, apoptosis of bystander lymphocytes, and increases in levels of proinflammatory cytokines. Most importantly, dysregulation of circulating levels of fibrinogen, protein C activity, and antifibrinolytic proteins and deposition of fibrin in tissues demonstrated both biochemical and microscopic evidence of disseminated intravascular coagulation.Conclusions. These findings suggest that the outbred guinea pig model recapitulates ZEBOV infection of primates better than inbred rodent models, is useful for dissecting key events in the pathogenesis of ZEBOV, and is useful for evaluating candidate interventions prior to assessment in primates.